Exam 3 Flashcards
What is the anatomy of the female reproductive system and what is the menstrual cycle?
Ovary -> Fallopian tube -> Uterus -> Cervix -> Vagina
Menstrual cycle -
Following the menses, the proliferative phase begins, where the endometrium grows. This is part of the follicular phase. Progesterone stays low during this phase, but estrogen rises pretty fast. Then, LH and FSH both spike, the follicle bursts, and ovulation occurs. Estrogen drops, and progesterone rises as the luteal phase continues (corpus luteum grows). Then, progesterone and estrogen both drop right before we return to the beginning of the cycle and menses occurs.
What role do hormones have in controlling the menstrual cycle?
Follicular phase -
As GnRH is secreted, FSH & LH get secreted. Increase of FSH stimulates the growth of the follicle, which stimulates production of estrogen. Around day 12, a peak of LH and FSH results in ovulation.
Luteal phase -
LH is responsible for this phase. Progesterone, secreted during growth of corpus luteum, changes the uterine lining & prepared the body for the formation of embryo. If no pregancy occurs, corpus luteum will dissintegrate, which lowers progesterone and estrogens, and the cycle starts over again.
What are the therapeutic roles of estrogen, progesterone, and gonadotropin releasing hormone?
Estrogen - Breast cancer palliation (only those that have learned to grow without estrogen), uremic bleeding, prevention of post-menopausal osteoporosis, menopause (vasomotor symptoms), vulvar and vaginal atrophy, female hypogonadism, ovarian failure, abnormal uterine bleeding, and contraception.
Progesterone - Long-term prevention of pregnancy, treatment of heavy menstrual bleeding, emergency contraception, amenorrhea, endometriosis.
Gonadotropin releasing hormone - Menorrhagia, endometriosis, premenstrual dysphoric disorder (PMDD).
What are the definitions of premenopausal, perimenopausal, and postmenopausal?
Premenopause - The time period of endocrine changes before cessation of menstruation.
Perimenopause (Climacteric) - The period of endocrine chnages surrounding the menopause. Ex. cycle may be weird. This can last for 2-7 years around menopause.
Postmenopause - The time period of endocrine changes after cessation of menstruation.
How can you evaluate a patient’s risk-benefit profile for hormonal treatment of menopausal symptoms?
Estrogen only - For women who are under 60 and within 10 years of menopause, there is a favorable risk-benefit profile. We find this by comparing the patients who were treated with estrogen v. placebo. The risk goes up as age and time since menopause goes up.
Estrogen + Progestin - Same findings were found as estrogen monotherapy.
How would you design an individual treatment plan using pharmacologic options for menopausal vasomotor symptoms?
The preferred route for MHTs is: Transdermal estrogen +/- progestin. This is because it causes less thromboembolic risk, stroke, heart attack, headache, and breast tenderness. Some side effects are skin irritation or skin transfer.
Alternatives:
- Oral estrogen +/- progestin
- Systemic vaginal estrogen +/- progestin.
- Bazedoxifene + Estrogen: Avoid if vaginal bleeding, less breast tenderness, less altered mood.
How would you evaluate a treatment plan on the basis of a patient’s response to pharmacologic management of menopausal symptoms?
- Evaluate patients annually and review comorbidities.
- Consider period trials of tapering, stopping, or changing to safer low-dose transdermal routes.
Under which circumstances should non-hormonal therapies for menopausal symptoms be considered?
Systemic MHTs should be avoided in women with high 10-year CVD and/or breast cancer risk. If they are experiencing genitourinary symptoms, low-dose vaginal estrogen or other treatments can be tried.
Transdermal administration is okay if they are within 10 years since menopause & CVD risk is 5-10%.
What is premature menopause?
This is when menopause happens before the age of 40. This can happen due to a hysterectomy, radiation therapy, and chemotherapy. This leads to a higher risk of mortality and morbidity.
What are the physiologic, surgical, and other causes of menopause?
Physiologic - Extensive deterioration of the follicular cells and ova with aging. The low estrogen and progesterone levels cause an increase in FSH and LH.
Surgical - removal of ovaries.
Other - Breast cancer chemotherapy.
What are the symptoms of menopause including vasomotor symptoms and gentiourinary syndromes?
Vasomotor symptoms (50-87%) - Hot flashes, night sweats.
Genitourinary syndromes (27-84%) - Vulvovaginal atrophy, urinary tract dysfunction, sexual dysfunction, urinary frequency & urgency.
What is the benefit of intravaginal products for estrogen monoreplacent? What’s the difference between Estring and Femring?
Ex. Vaginal cream, vaginal insert, vaginal tablet, vaginal rings
Benefit - Effect is so localized that even with uterus intact, we can use these as monotherapy.
Femring - Need to give with progesterone because it can work systmically.
Estring - Doesn’t have high enough concentration for systemic effects, so this is still good for monotherapy.
What is the downside of oral products for estrogen monoreplacement?
Ex. Premarin, Menest, Estrace
Because they go are systemic, they can cause a higher incidence of side effects.
What was found during the Women’s Health Initiative study when looking at hormonal therapy for post-menopausal women?
Women with an intact uterus were associated with a higher risk of breast cancer and no significant difference in cancer mortality.
Women without intact uterus had significantly lower risk of break cancer incidence and no difference in cancer mortality.
Also, it was found that patients with estrogen + progesterone had higher risk of CHD and cancer. So many think the progesterone is causing the heart diseases/cancer.
What are the indications and contradictions for MHT? When should MHT be recommended?
Indications for MHT - Vasomotor symptoms, vulvovaginal atrophy, and osteoporosis prevention (not the main indication but MHT can help).
Absolute contraindications - Unexplained vaginal bleeding, pregnancy, estrogen-dependent malignancies, stoke, etc.
Relative contraindications - Uterine leiomyoma, diabetes, migraines with aura, seizure disorders, etc.
Recommended: Initiation of treatment should be limited to women younger than 60 OR women who have had their last period within 10 years. Start at a low dose, then titrate up.
Estrogen increases the risk of all of the following except…
- Stroke
- Fracture
- Heart attack
- Venous thromboembolism
- Breast cancer
Fracture (+ colorectal cancer)
What are the different combined estrogen and progestins for menopause?
Continuous cyclic therapy - Estrogen is administered daily and the progesterone is administered at least 12-14 days of a 28 day cycle. Ex. Premphase (oral), Combipatch (transdermal)
Continuous long cycle - Estrogen is administered daily, progesterone is administered for 12-14 days every other month. This results in less bleeding times (6 instead of 12).
Continuous combined - Daily estrogen + progesterone. This is recommended for women > 2 years post-final menstrual period. Ex. Prempro (oral), ClimaraPro (transdermal).
Intermittent combined - 3 days of estrogen, 3 days of estrogen + progestin, 3 days estrogen, etc. Ex. prefest (oral)
What are some progestin-only products for menopause?
Oral -
- Medroxyprogesterone (Provera)
- Norethindrone acetate (Aygestin)
- Micronized progestin (recommended!!)
Vaginal/Intrauterine
- Levonorgestrel (Mirena IUD)
- Progesterone gel (Crinone)
What’s the estrogen + SERM product for menopause?
Duavee (Oral); Conjugated estrogen and bazedoxifene
- SERM is non hormonal & helps decrease the risk of endometrial cancer.
- Can be used to treat for menopausal symptoms and to prevent bone loss in women with an intact uterus.
What are the alternatives for vasomotor symptoms in menopausal treatment?
Phytoestrogens - Plant estrogens that are less potent than synthetic estrogens. Ex. Isoflavones, lignans, coumestans. Doesn’t hurt to try, and may alleviate some symptoms, but we wouldn’t really recommend.
Black cohosh - Claim to help with post-menopausal symptoms, but data shows it’s no better than placebo and can cause hepatotoxicity if used for more than 6 months.
Dong Quai - May increase risk of bleeding.
Gabapentin/Pregabalin - Used for the mood swings and neuropathic pain, but may cause pretty bad dizziness/sedation.
Clonidine - Used for HTN, causes dizziness, sedation, dry mouth. (not for women with low BP)
What is the drug of choice if the woman doesn’t want hormonal therapy for vasomotor symptoms of menopause?
SSRIs/SNRIs
Selective serotonin reuptake inhibitors - Have shown to help with vasomotor symptoms, but not more effective than hormonal therapy. Ex. Paroxetine (Brisdelle,Paxil). These work really well, especially if they’ve also experienced the mood changes.
Serotonin and Norepinephrine Reuptake Inhibitors - Venlafaxine, Desvenlafaxine, may take a while for the meds to kick in, important to avoid drastic stopping of meds due to withdrawal.
What is bio-identical hormone replacement therapy?
Compounds with mix of estradiol, estrone, estriol, and progesterone. It’s trying to mimic the hormone that is in the body in the woman’s 20s.
There’s no data to support the use of these products. We generally don’t recommend this.
Bijuva (oral) is the only one that is FDA approved, but it’s very pricey.
What’s the first and second lines of treatment for Genitourinary syndrome of menopause?
First: non-hormonal; lubricants (short duration of action, frequent applications needed), vaginal moisturizers (2-3 applications/week)
Second: (estrogen) Topical (cream, tablet, ring), low dose oral contraceptive
What are the 2 options for treatment of moderate-severe dyspareunia?
Ospemifene (Osphena) - SERM; Black Box Warning of endometrial cancer, stoke, and VTE; Hot flashes is a common side effect.
Prasterone (Intrarosa) - Inactive DHEA is converted to active estrogens and androgens. Contraindicated in pts with undiagnosed vaginal bleeding and avoid is they have a history of breast cancer.
What are some principles of menopausal hormone therapy?
The treatment should be tailored to the individual pt and will vary according to age, symptom severity, medical profile, risk/benefit ratio, etc.
There should be a shared decision-making approach.
What are the general approaches to management of menopausal symptoms?
First, determine if there’s evidence of moderate/severe menopausal symptoms.
Moderate/severe vulvovaginal atrophy: consider hormonal therapy.
- If yes, use vaginal estrogen prep (endometrial monitoring if uterus is intact) or ospemifene or prasterone; Use estradiol acetate ring or systemic estrogen (plus progesterone) if also vasomotor symptoms
- If no, use nonhormonal vaginal moisturizer
Moderate/severe vasomotor symptoms: consider hormonal therapy.
- If yes, use oral or transdermal estrogen or estradiol acetate intravaginal ring (plus progesterone if uterus intact); Use bazedoxifene/conjugated estrogens (only if uterus is intact)
- If no, use SSRI or SNRI antidepressant, gabapentin/pregabalin, or clonidine; If taking tamoxifene, avoid paroxetine or fluoxetine or other moderate or strong CYP2D6 inhibitors.
What are the hormones produced by the hypothalamus (5) and by the pituitary gland (4)?
Hypothalamus:
- GHRH: Growth hormone releasing hormone
- SST: Somatostatin
- TRH: Thyrotropin releasing hormone
- CRH: Corticotropin releasing hormone
- GnRH: Gonadotropin releasing hormone
Pituitary:
- GH: Growth hormone (acts on many peripheral tissues)
- TSH: Thyroid stimulating hormone (acts on thyroid)
- ACTH: Adrenalcorticotropic hormone (acts on adrenal cortex)
- FSH, LH: Follicle stimulating hormone, luteinizing hormone (acts on gonads)
How is the synthesis of each of hypothalamus/pituitary hormones stimulated (4) or suppressed (2)?
Stimulators of the hypothalamus: GHRH, TRH, CRH, GnRH
Suppressors: DA, SST
Which hormones are produced by the anterior (6) (and posterior pituitary (2))?
Anterior pituitary:
- Growth hormone (activate JAK/STAT pathway)
- Prolactin (activate JAK/STAT pathway)
- TSH, FSH, LH (activates GPCRs, have common α chain)
- ACTH (activates GPCRs)
Posterior pituitary:
- Vasopressin
- Oxytocin
How can you sort peptide hormones based on their structural similarity?
GH - Small protein with 2 disulfide bonds. Similar to prolactin. It’s an α-helix bundle.
Thyroid stimulating hormone, FSH, and LH all have that same α chain, so you end up differentiating by the beta strand.
What are the functions of GH and IGF-1?
GH (growth hormone): Required to attain adult size. Increases lean body mass, reduces central adiposity (increases metabolism of fat), reduces insulin sensitivity.
IGF-1 (insulin-like growth factor 1): GH stimulates IGF-1 which is what promotes the growth in the liver, bone, cartilage, and muscle.
How can you identify recombinant forms of each peptide hormone (2)?
rhGH (somatotropin) - recombinant GH, α-helix bundle
rhIGF-1 (mecasermin) - Used in the treatment of IGF-1 deficiency (ex. if GH doesn’t bind to its receptor) . Its structure is a complex with an IGF-1 binding protein to increase the half life.
What are the structural and functional similarities and differences between LH, FSH, and hCG?
FSH - directs ovarian follicle development in women, regulates spermatogenesis in men, and stimulates the conversion of testosterone to estrogens in both.
LH - stimulates androgen production in the follicular phase and controls est/prog production in the luteal phase for women, stimulates androgen production in men.
hCG - produced in the placenta during pregnancy, controls est/prog production during pregnancy. The structure is nearly identical with LH.
FSH, LH, and hCG are all heterodimeric proteins that have the same α chains, but different β chains (LH and hCG are nearly identical tho).
What are the different preparations of gonadotropins that are used clinically? (Menotropins, urofollitropin, follitropin α & β, Lutroprin α, hCG, and Choriogonadotropin).
Also what are 2 main uses of gonadotropins?
Menotropins - Mixture of FSH and LH taken from urine of postmenopausal women. This is the most commonly used ones.
Urofollitropin (uFSH) - Only FSH from postmenopausal women; The LH activity is removed during purification.
Follitropin α & β - Recombinant forms of FSH.
Lutropin α - Recombinant form of LH. Used for stimulation of follicular development in infertile women with LH deficiency, but it was discontinued due to cost.
hCG - extracted from pregnant women and has the same activity as LH.
Choriogonadotropin α (rhCG) - recombinant hCG
Uses:
- Ovulation induction: This is usually for patients that fail to respond to other treatments like Clomiphene.
- Male infertility
What are the effects of pulsatile and continuous administrations of GnRH and its analogs?
Pulsatile - stimulates the production and release of LH and FSH.
Continuous - it would suppress FSH and LH due to desensitization (or down regulation).
What are the structural differences between vasopressin and oxytocin?
Only 2 amino acids are different: AA 3 and 8.
There’s some cross-activity, so if oxytocin levels are high, it’s not uncommon to see vasopressin effects.
What are the physiological functions of vasopressin? (3)
- Increases reabsorption of water from tubular filtrate by increasing water permeability in the cells in renal collecting tubes (antidiuretic activity).
- Constricts blood vessels to raise blood pressure (vasopressor activity).
- Increases levels of Von Willebrand factor and coagulation factor VIII.
What is the difference between the physiological role between vasopressin receptor types and the receptor specificity of desmopressin?
Desmopressin is a long-acting synthetic analog of vasopressin due to the modification at AA 1 and 8.
Desmopressin has very minimal V1 receptor activity, meaning it doesn’t have much vasoconstriction activity. It much more of a selective antidiuretic than vasopressin.
What are the clinical uses of vasopressin (2)/desmopressin (2)?
Vasopressin:
- coagulopathy in hemophilia A (clotting defect)
- von Wilderbrand’s disease (low clotting)
Desmopressin:
- pituitary diabetes insipidus
- nocturnal enuresis
What are the adverse effects of vasopressin (3 + extra)?
- Water intoxication (can lead to hyponatremia, drowsiness, headache, etc.)
- Abdominal cramping
- Allergic reaction
Use with extreme caution in person with cardiovascular diseases
What is the physiological function of oxytocin? (4)
- Uterine contraction in labor and delivery (contracts uterine smooth muscle, stimulates the release of prostaglandins and leukotrienes that augment uterine contraction)
- Milk ejection in lactating women (contracts myoepithelial cells surrounding mammary alveoli)
- Acts through a GPCR to increase cytosolic Ca2+ levels resulting in smooth muscle contraction
- Improves social bonding and trust
What are the clinical uses of oxytocin? (3)
- Induction and stimulation of labor
- Control of uterine hemorrhage after delivery
- Enhancement of milk ejection
What are the adverse effects of oxytocin?
- Excessive stimulation of uterine contraction before delivery (can cause fetal distress, placental abruption, uterine rupture, and trauma to the birth canal)
- Activation of vasopressin receptors by overdose of oxytocin (can cause fluid retention, water intoxication, and hyponatremia)
What are the contraindications of oxytocin? (3)
- Fetal distress
- Abnormal fetal presentation
- Cephalopelvic disproportion
What is the ovulation induction protocal?
- FSH precautions during follicular phase - to prevent premature surge in LH, the effects of endogenous GnRH need to be blocked by continuous administration of GnRH or GnRH receptor antagonist.
- Administration of hCG leads to ovulation which leads to insemination or oocyte retrieval.
- Hormonal support during the luteal phase (typically by exogenous progesterone).
What are the clinical uses of FSH and LH stimulation (2, pulsatile GnRH) and suppression (4 continuous GnRH)?
Stimulation: Pulsatile GnRH
- Female infertility: uses pump to give pulsatile dosing.
- Male infertility: Uses pump to give pulsatile dosing. Used for men with hypothalamic hypogonadotropic hypogonadism. This isn’t the preferred treatment.
Suppression: continuous GnRH
- Controlled ovarian hyperstimulation to suppress LH surge
- Endometriosis (reduces production of est/prog)
- Prostate cancer (reduces testosterone levels)
- Central precocious puberty
What are 2 clinical uses for GnRH receptor antagonists?
These act as competitive antagonists (Genirelix, Cetrorelix, Abarelix, etc.)
- Controlled ovarian hyperstimulation: Produce an immediate antagonist effect.
- Advanced prostate cancer
What is significant about the relationship between prolactin and dopamine?
They antagonize eachother. As dopamine goes up, prolactin goes down, and vice versa.
Hyperprolactinemia can be treated pretty well by dopamine agonists.
What are the physiological effects of thyroid hormones on growth and development, metabolic effects, thermogenesis, and cardiovascular effects?
- Growth and development: It’s essential for brain development (without T3, cretinism can happen) and promotes protein synthesis
- Metabolic effects: Increases basal metabolic rate (BMR) and oxygen consumption
- Thermogenesis: Increases resting heat production
- Cardiovascular effects: Increases catecholamine sensitivity
What are the differences between T3 and T4 in their structures and activities?
T3 - Has 3 iodines; More potent
T4 - Has 4 iodines; Produced 10x more than T3
What are the specific locations of particular reactions in thyroid hormone synthesis? (steps A-H)
A. Get iodine (I2) from diet and it converts to I- iodide in the stomach
B. Iodide active transport into thyroid follicular cell by Na+-I- symporter (NIS)
C. Iodide passively passes down into the follicular colloid through the pendrin transporter. Then it’s oxidized by thyroid peroxidase to I^0 at the apical membrane.
D. Iodide-free thyroglobulin is transported to the apical membrane
E. Thyroglobulin is iodinated by thyroid peroxidase at one or two positions, forming the hormone precursors MIT and DIT
F. MIT + DIT = T3 and DIT + DIT = T4. This coupling is dependent on thyroid peroxidase
G. Thyroid hormone-containing thyroglobulin is retrieved back into the cytosol as colloid droplets by pinocytosis
H. Lysosomal exopeptidases cleave T3 or T4 from thyroglobulin and the hormones are released into circulation where T4 can be converted to T3 by 5’deiodinase.
What is the role of deiodination in metabolism of thyroid hormones?
Deiodination is when T4 or T3 is conjugated to form glucuronide or sulfate with the phenolic group. It is then excreted in the bile.
What’s the difference between toxic goiter and nontoxic goiter?
A goiter is an enlargement of the thyroid gland due to a persistent rise in TSH (this means that TSH is low, so there’s no negative feedback, which causes a rise in TSH)
Toxic - Diffuse toxic goiter is seen in Graves’ disease. Toxic uninodular goiter and toxic multinodular goiter is seen with an adenoma producing excess T3
Nontoxic - Thyroid enlargement that may be seen in hypothyroidism
What are the symptoms of hypothyroidism and hyperthyroidism?
The symptoms are exactly opposite from each other. Hypo slows everything down, hyper speeds everything up.
Hypothyroidism - Deficiency of thyroid hormones
- Decrease in metabolic rate presented by fatigue, mental dullness, lethargy, inattention
- Defective thermoregulation
- Nontoxic goiter
- Dwarfism and mental retardation (cretinism) in infants and children
- Myxoedema coma
Hyperthyroidism - Excessive levels of thyroid hormones
- Excessive metabolism presented by poor thermoregulation and weight loss
- Increased heart rate and cardiac output
What is the pathology of Hashimoto’s thyroiditis and Graves’ disease?
Hashimoto’s thyroiditis - Autoimmune disease that destroys the thyroid gland leading to hypothyroidism
Graves’ disease - Autoimmune disease that involves thyroid-stimulating IgG. This can result in enlargement of the entire thyroid gland (diffuse toxic goiter)
What drugs are used for thyroid hormone replacement therapy?
Levothyroxine (T4) - Converted to T3 intracellularly. Slow onset with long half life. Takes 6-8 weeks to reach steady state.
Liothyronine (T3) - Rapid onset, short duration of action, requiring multidosing. Only used in emergency situations.
Liotrix (4:1 mix of T4 and T3) - More expensive and not more effective than T4 administration.
What are the treatment options for hyperthyroidism? (5 main ones)
- Antithyroid drug therapy - Thioamides
- Thyroidectomy - requires lifetime thyroid supplementation
- Destruction of the gland with radioactive iodine
- Anion inhibitors (competitive inhibitor of iodide, ex. SCN-)
- Symptom treatment: Propranolol to slow heartbeat, Diltiazem for tachycardia, Barbiturates lower T4 levels and act as sedatives, Bile acid sequestrants lower T4 levels.
What channels are responsible for the sinoatrial action potential?
Ca2+ channel is responsible at first
K+ channel is responsible last
What is the effect of norepinephrine and acetylcholine on sinoatrial action potential?
Norepinephrine - (released by sympathetic nerve) Binds to β-adrenergic receptor, which increases cAMP, which activates the HCN channel. This activation increases diastolic Na+ conductance, which shortens the time until the next spike. So this increases heart rate.
Acetylcholine - (released by vagal nerve) Binds to M2, releasing Gβγ from Gα. Gβγ activates GIRK channel, which causes hyperpolarization leading to delayed time until the next spike. So this decreases heart rate.
What is the mechanism by which thyroid hormones increase heart rate?
T3 increases the transcription of the β-adrenergic receptor and HCN channel, which are both involved in increasing the heart rate.
How do thioamides help with hyperthyroidism? What are two examples of thioamides?
Thioamides inhibit thyroid peroxidases. They block iodine organification and block the coupling of the iodotyrosines.
Ex. Methimazole, Propylthiouracil
Why would Iodide itself be used to treat hyperthyroidism?
Large doses of I- inhibits its own uptake, organification, release of thyroid hormones, and it decreases vascularity of the thyroid gland.
However, these are only used short-term, like in prep for a thyroidectomy.
