Estrogens/progestins pharmacology

What are the normal pharmacologic effects of 17beta estradiol?

Strengthens bone, heightens HDL, lowers LDL, reduces menopause symptoms.

What are the major metabolites of 17beta estradiol? Are they pharmacologically active?

Estrone/Estriol, minorly active

What happens after phase I metabolism of 17beta-estradiol by CYP450 enzymes, what types of Phase II conjugation productions are formed? How does enterohepatic cycling play a role in blood levels of estrogen? What would happen to blood levels of estrogen if enterohepatic cycling was disrupted?

Metabolites are sulfated/glucuronidated. Glucuronides are enteropeatically recycled with gut flora. Without recycling blood levels could be lower than expected.

What are the normal pharmacologic effects of progesterone?

Progesterone (towards gestation) prepares the reproductive tract for implantation (all steroid hormone receptors are nuclear).

Once pregnant, it maintains pregnant state (can be done to protect against the loss of pregnancy IM QD, also could use hydroxyprogesterone caproate IM Q7 [week 20-36]). Promotes fat deposition.

Which progestins are sometimes used for the maintenance of pregnancy? By what route and dosing frequency are they administered?

hydroxyprogesterone Caproate IM Q7 days for weeks 20-36

What are the adverse pharmacologic effects of progesterone?

(Headache, Breast Pain, HTN, Weight Gain, Nausea (High Dose)

Describe the estrogen, progesterone and androgen receptors and the classical model of receptor activation. Describe the non-genomic model of estrogen, progesterone and androgen receptors. Where are those receptors found and what second messenger is involved? in other words, how does ER differ from mER? How does PR differ from mPR? How dies AR differ from mAR?

(Original receptors are nuclear, new ones were found to me Gs-GPCR. (E2, DHT, P main agonists). GPCR have rapid acting mechanisms compared to slow acting nuclear mechanisms.)

Describe which types of estrogens are used in HRT?

Why do many HRT medications for menopause not just contain estrogen but also progestin?

Describe the adverse effects associated with therapeutic estrogens. Contraindications associated with them?

17B-Estradiol, Ethinyl Estradiol, Estradiol Valerate, Conjugated Estrogens.
Estrogen without progesterone can cause ovarian/breast cancer.

AE: Breast cancer / uterine cancer risk, risk of MI/Stroke, risk of blood clots, risk of migraine, N/V, fluid retention/edema, gall bladder disease, lowered bilirubin excretion, decreased B6 abs.

Describe the HRT formulations premarin, prempro, femhrt?

Premarin - Conjugated E1 from horse urine,
Prempro - Premarin + MPA,
Femhrt - Ethinyl Estradiol + Norethindrone.

What happens to the release of LH and FSH by the pituitary when plasma levels of both estrogen and progesterone are high, such as during pregnancy?

Why would inhibition of ovulation be useful if there is a developing baby in the uterus?

FSH/LH is inhibited during pregnancy. You need to ensure a second follicle isnt matured and released while already pregnant.

What are the proposed mechanisms of action for the combination oral contraceptives?

Inhibit ovulation, increase cervical mucus, change uterine tube secretions

How about for the progestin-only OCs?

Increase cervical mucus, change uterine secretions

What types of progestin-only products are available for contraception?

Pills, implants, IUD

What two types of agents do combination oral contraceptives (OCs) contain?

For most OCs, what is the standard dosing regimen? Of 28 tablets, how many are "active" and how many are "inert?"

What happens during the seven days of "inert" tablets?
Is the choice of combo OC universal? Or is it patient-specific?

Estrogen + Progestin (21 active / 7 inactive)
Break through bleeding
Choice of drugs is patient specific

Comment on some of the interesting adverse effects relating to transdermal administration or administration via vaginal ring.

transdermal administration leads to a 60% higher plasma level of estrogen than that observed after oral administration and may confer a higher risk of thromboembolism than oral administration
—also transdermal appears to be less effective in women >90 kg

Vaginal ring associated with higher incidence of vaginitis, vaginal discomfort, vaginal infections compared to other forms of contraception

Compared to estradiol, what is the chief pharmacokinetic advantage for ethinyl estradiol? How is the compound eliminated from the body? Does it undergo enterohepatic cycling?

yes, it does undergo enterohepatic cycling
Ethinyl estradiol keeps the compound as estradiol and not estrone. CYP450 oxidation, conjugation to sulfate/glucuronide and excreted.

Compared to progesterone, what is the chief pharmacokinetic advantage for norethindrone or other synthetic progestins?

It is more bioavailable and has higher potency.

With respect to the combination OCs, does either drug alter the pharmacokinetics of the other?

NO.

What is the difference between monophasic, biphasic, triphasic and four phasic OCs? What is estradiol valerate? Is it a drug or a prodrug?

Prodrug, phasic is dose changes during contraceptive cycle.

Long-duration contraception with progesterone-only agents can be achieved using

parenteral routes of administration such as implantable or intramuscular preps.

Which progestin is available as a subcutaneous implant

etonogestrel

Which progestin is available as an i.m. injection

medroxyprogesterone acetate

Why are progestin-only contraceptive tablets a possible option for nursing mothers?

Estrogen hormones inhibit lactation

Which progestins are the most androgenic? Adverse effects that may be associated with them? Which progestins are anti-androgenic? Which of these progestins (MPA, levonorgestrel, norgestrel, norethindrone, dienogest, drospirenone) is: Anti-androgenic? Slightly androgenic? Highly androgenic? Which one is also anti-mineralocorticoid and associated with hyperkalemia in some patients?

Levonorg > Norg > MPA. Hirsuitism, acne, baldness. Drospironone/dienogest. D drugs are anti-androgen, slightly is MPA/norethindrone, levonorg/norg is high androgen. Drospirenone is hyperkalemic.

What possible drug-drug interactions can be predicted in patients taking oral contraceptives, particularly in patients taking oral contraceptives and inducers of CYP450s (eg. Rifampin, griseofulvin, carbamazepine, phenytoin)? What about oral contraceptives and St. John's Wort?

CYP450-3A4 inducers increase the metabolism of hormones.

What is so unique about drospirenone? Does is have antiandrogenic activity? Does it have antimineralocorticoid activity? Should women with renal failure take an oral contraceptive that contains drospirenone?

Antiandrogenic progestin, yes, no.

Compared to unopposed estrogen, what happens to the risk of endometrial cancer in patients taking estrogen + progestin oral contraceptives?

It is lower relative to Estrogen alone, but higher than baseline.

Do emergency contraceptives have potential for extreme nausea?

Yes, high dose progestins can cause extreme nausea.

What is the MOA of emergency contraception by the PR agonist levonorgestrel?

Levonorg --> High dose of progestin inhibits GnRH/FSH/LH preventing ovulation.

SPRM ulipristal acetate

emergency contraceptive moa

Unipristal --> Inhibits LH release from the hypothalamus/pituitary axis.

What is the pharmacologic difference between emergency contraceptives and mifepristone?

What types of adverse effects are associated with the latter? Why coadministration of mifepristone with misoprostol?

Mifepristone --> Abdominal pain, heavy vaginal bleeding. Mifepristone terminates the abortion via progesterone antagonism, misoprostol induces vaginal contractions.

Clomiphene is used for and it is a ___ ?

Used for infertility it is an ovulation inducer

Clomiphene any rare but serious adverse effects

chance of multiple gestation (~8% incidence when fertility occurs) or ovarian hyperstimulation syndrome.

AE: Hot flashes, ovarian hyperstimulation syndrome

What is ovarian hyperstimulation syndrome?

Ovarian hyperstimulation syndrome (OHSS) is the most significant side effect associated with clomiphene, and includes gross ovarian enlargement, abdominal pain, nausea/vomiting/diarrhea] . When it happens, this syndrome develops rapidly within 24 hours to several days after treatment. [Note that a typical course of clomiphene treatment usually lasts for 5 days;].

Clomiphene MOA

SERM that interferes with negative feedback on the hypothalamus increasing probability of ovulation.