Drugs To Use For Women’s Health Issues

Question 1

Estrogens

Estradiol

Answer 1

most potent estrogen; secreted in the ovary by the premenopausal woman

Question 2

Estrogens

Estrone

Answer 2

metabolite of estradiol; 1/3 of the potency of Estradiol; primary estrogen in the post- menopausal woman; generated from conversion of androstenedione in the peripheral and adipose tissues

Question 3

Estrogens

Estriol

Answer 3

another metabolite of Estradiol; must less potent than Estradiol; principal estrogen produced by the placenta

Question 4

Estrogens

Conjugated Equine Estrogen

Answer 4

sulfate esters of Estrone + Equilin is a common oral estrogen used as HRT [Premarin]

Question 5

Estrogens

Other estrogens

Answer 5

Plant derived estrogens

Synthetic estrogens—ethinyl estradiol—undergoes less liver metabolism than naturally occurring estrogens, so can be safely used at low doses

Nonsteroidal compounds that bind to estrogen receptors [have both estrogen and anti-estrogen effects] are called SERMs [Tamoxifen, Raloxifene (Envista)]

Question 6

Estrogens

MOA and Therapeutic Uses

Answer 6

MOA—activated steroid-receptor complex interacts with nuclear chromatin to initiate
hormone specific RNA synthesis

Used for postmenopausal hormone therapy, contraception, replacement in the
premenopausal patients who are deficient [hypogonadism, premature menopause,
surgical menopause]

Question 7

Postmenopausal Hormone Therapy

Answer 7

Used in vasomotor instability, vaginal atrophy

If the woman has a uterus, progestogen must be included to reduce the risk of
endometrial cancer

If the woman has had a hysterectomy, unopposed estrogen is used—progestins may have negative effects on the lipid panel

ADE are less than in those using estrogens for contraception

Estradiol by patch or gel is also effective for postmenopausal symptoms

Risks of HRT—increased risk of CV events and breast cancer

Women with only GU symptoms are best treated with vaginal estrogens

Question 8

Estrogens Androgens

Other Uses

Answer 8

Contraception

Combination of estrogen and
progestogen is used
-Orally
-Transdermal
-Vaginal

Other Entities

Primary Hypogonadism
-Estrogen that mimics natural cycle +
progestogen to stimulate development of
secondary sexual characteristics
-Must be continued until after growth has
been completed

Premature Menopause
-Estrogen + progestogen replacement is
used

Question 9

Pharmacokinetics

Naturally Occurring Estrogens

Answer 9

Absorbed though the GI tract, skin & mucous membranes

Taken orally, estradiol is rapidly metabolized by the liver; micronized estradiol is available and has better bioavailability

Question 10

Pharmacokinetics

Synthetic Estrogen Analogs

Answer 10

Ethinyl estradiol, mestranol & estradiol
valerate are well absorbed after oral
ingestion

These are fat soluble, they are stored in
adipose tissues, from there they are slowly
released

Synthetic estrogen analogs have prolonged action & are more potent than
natural estrogens

Question 11

Pharmacokinetics
Estrogens

Metabolism

Answer 11

Estrogens are transported to the blood bound to albumin or SHBG; bioavailability of oral estrogen is low [because of 1st pass metabolism]; to reduce 1st pass effects—give the drug transdermally, intravaginally or by injection

They are then hydroxylated in the liver to derivatives that are then glucuronidated or sulfated

The parent drugs and the metabolites are excreted into the bile and are then reabsorbed through the enterohepatic circulation; inactive products are excreted in the urine

Question 12

Estrogens

Adverse Effects

Answer 12

Nausea
Breast tenderness
Elevation of BP
Elevation of triglycerides
Peripheral edema
Increased risk of VTE and MI
Increased risk of breast and endometrial cancer [endometrial cancer risk reduced by
concomitant use of a progestin]

Question 13

Selective Estrogen Receptor Modulators

Answer 13

Estrogen related compounds that display selective agonism or antagonism for estrogen receptors—depending on the target tissue

-Tamoxifen
-Toremifene [Fareston]
-Raloxifene [Evista]
-Clomiphene [Clomid]
-Ospemifene [Osphena]

Question 14

Selective Estrogen Receptor Modulators

Mechanism of Action

Answer 14

Tamoxifen, Toremifene and Raloxifene compete with estrogen for binding to the estrogen receptor in the breast tissue
-Raloxifene also acts as an estrogen agonist in the bone, leading to decreased bone resorption, increased bone density and decreased vertebral fractures. Unlike Tamoxifen and estrogen, Raloxifene does not have appreciable estrogen receptor agonist activity in the endometrium [so no increased risk of endometrial cancer]
-Raloxifene also lowers total and LDL cholesterols

Clomiphene acts as a partial estrogen agonist and interferes with the negative feedback of estrogens on the hypothalamus
-These effects increase secretion of gonadotrophin releasing hormone and gonadotropins—stimulating ovulation

Question 15

SERM

Uses and Pharmacokinetics

Answer 15

Tamoxifen—metastatic breast cancer; add
on therapy after mastectomy or XRT for
breast cancer; prevention of breast cancer in
those at high risk

Raloxifene—prevention of breast cancer in
those at high risk; prevention and treatment
of osteoporosis in postmenopausal women

Clomiphene—used for infertility from
anovulatory cycles

Ospemifene—treatment of dyspareunia from menopause

Question 16

SERM

Pharmacokinetics

Answer 16

SERMs rapidly absorbed after PO
administration

Tamoxifen—metabolized by CYP450
isoenzymes

Raloxifene—rapidly converted to glucuronide conjugates through 1st pass metabolism; undergoes enterohepatic cycling—main route is excretion through the bile into the feces

Question 17

Progestogens

Answer 17

Progesterone—natural progestogen; produced in response to LH in women & by the testes in men; also produced by adrenal cortex in both sexes

Question 18

Progestogens

MOA

Answer 18

In women—progesterone promotes development of secretory endometrium that
accommodates implantation of newly forming embryo

High levels released during the luteal phase inhibit the production of gonadotropin and
prevent ovulation—if conception occurs, progesterone continues to be produced to
maintain the endometrium & reduce the uterine contractions

If conception does not occur, release of progesterone from corpus luteum stops—this decline causes menstruation to take place

Question 19

Progestogens

Therapeutic Uses

Answer 19

Contraception
Treatment of hormone deficiency
Control of DUB, dysmenorrhea, endometriosis management and infertility
For contraception—they are combined with estrogens
Synthetic progestogens—progestin used in contraception are more stable to first pass
metabolism
Desogestrel, Dienogest, Drospirenone, Levonorgestrel, Norethindrone, Norethindrone acetate, Norgestimate, Norgestrel
Medroxyprogesterone acetate injection [this agent is used orally as part of HRT]

Question 20

Progestogens

Pharmacokinetics

Answer 20

Micronized progesterone is rapidly
absorbed after oral ingestion

Metabolized by liver; glucuronidated
metabolite is excreted by the kidney

Oral medroxyprogesterone acetate has a
½ life of 30 days; when given IM or SC the
½ life is about 40-50 days and gives
contraceptive activity for approximately
90 days; other progestins have ½ lives of 1-
3 days allowing for once a day dosing

Question 21

Progestogens

ADEs

Answer 21

Headache
Depression
Weight gain
Changes in libido

Progestins that are derived from 19-
nortestosterone possess some androgenic
activity because of their similarity to
testosterone—can cause acne and hirsutism

Those that are less androgenic—norgestimate and drospirenone, are preferred in women with acne [can raise K+]

Question 22

Antiprogestins

Answer 22

Mifepristone [RU-486]

Progesterone antagonist with partial agonist activity
Use of this drug early in pregnancy usually in abortion due to interference with the progesterone
Often combined with the prostaglandin analog Misoprostol [PO or intravaginally] to induce contractions—uterine bleeding and the possibility of incomplete abortion

Question 23

Contraceptives

Answer 23

Interference with ovulation—most common
pharmacologic intervention for preventing
pregnancy

Question 24

Major Classes of Contraceptives

Combined Oral Contraceptives [COC]

Answer 24

Most common estrogen in COCs—ethinyl estradiol

Most common progestins in COCs—norethindrone, norethindrone acetate, levonorgestrel, desogestrel, norgestimate and drosperidone

Question 25

Combined Oral Contraceptives [COC]

Answer 25

Combination on an estrogen & a progestin Monophasic combination pills contain a constant dose of estrogen and progestin over 21-24 days Triphasic COC attempt to mimic the natural female cycle—most contain a constant dose of estrogen with increasing doses of progestin given over 3 successive 7 day periods Active pills are taken for 21-24 days, followed by 4-7 days of placebo, for a total regimen of 28 days—withdrawal bleeding occurs during the hormone free period Extended cycle contraception [84 pills followed by 7 days of placebo] results in less frequent withdrawal bleeding

Question 26

Patches/Rings Estrogen Transdermal Patch

Answer 26

Ethinyl Estradiol and Norelgestromin Patch is applied weekly for 3 weeks to abdomen, torso or buttocks 4th week no patch is worn Efficacy comparable to COCs in women weighing <90 kg Total estrogen exposure greater than with COCs

Question 27

Patches/Rings Estrogen Ring

Answer 27

Vaginal ring of Ethinyl Estradiol and Etonogestrel Ring left in place for 3 weeks, then left out for r1 week Efficacy, contraindications & ADEs similar to COCs

Question 28

Progestins Pills Norethindrone—called “Mini Pill”

Answer 28

Taken daily Less effective than COCs; they may produce irregular menstrual cycles Can be used while breast feeding, can be used in those intolerant to estrogen, those that smoke or those with contraindications to estrogens

Question 29

Progestins Injections Medroxyprogesterone acetate

Answer 29

given IM or SC every 90 days ADE -Weight gain -Amenorrhea -Bone loss/osteoporosis Return to fertility may be delayed for several months after discontinuation Drug should not be used for >2 years unless patient is unable to use other methods

Question 30

LARCs—Progestin Based Implants

Answer 30

Subdermal Etonogestrel Ensures contraception for 3 years -Effect totally reversible when surgically removed ADEs—irregular menses; headaches Has not been studied in women >130% of IBW

Question 31

LARCs—Progestin Based IUDs Levonorgestrel releasing IUD system

Answer 31

Levonorgestrel releasing IUD system Lasts for 3-5 years Suitable for those who have contraindications to estrogens; avoid in patients with PID or hx of ectopic pregnancy

Question 32

Emergency Contraception

Answer 32

Reduces chance of pregnancy after an episode of unprotected or ineffectively protected intercourse Reduces chance of pregnancy to 0.2-3% High doses of Levonorgestrel or high doses of Ethinyl Estradiol + Levonorgestrel Should be taken ASAP after the intercourse—preferably within 72° Progestin only EC better tolerated than estrogen/progestin combinations Alternative -Progesterone agonist/antagonist— Ulipristal [Ella] can be used as EC within 5 days of unprotected intercourse

Question 33

Emergency Contraception MOA

Answer 33

Estrogens provide a negative feedback on the release of LH and FSH by he pituitary—preventing ovulation Progestins thicken cervical mucous, interfering with the transport of sperm Withdrawal of the progestin stimulated menstrual bleeding

Question 34

ADEs of Estrogens

Answer 34

Breast fullness Fluid retention Headache Nausea Elevated BP Thromboembolism Thrombophlebitis MI Stroke

Question 35

ADEs of Progestins

Answer 35

Depression Changes in libido Hirsutism Acne

Question 36

Androgens

Answer 36

Steroids that have anabolic and/or masculinizing effects in both men and women Testosterone—synthesized by Leydig cells in the testes & in smaller amounts by thecal cells in the ovaries and adrenal gland [in both sexes] Other androgens secreted by the testes—5 alpha dihydrotestosterone [DHT]; androstenedione, dehydroepiandrosterone [DHEA] Testosterone secretion by Leydig cells is controlled by gonadotrophin-releasing hormone from the hypothalamus, which stimulates the anterior pituitary to secrete LH and FSH Testosterone or its active metabolite [DHT] inhibits production of these specific trophic hormones Androgens are needed for—normal male maturation, sperm production, increased production of muscle proteins, Hbg. and decreased bone resorption

Question 37

Androgens MOA

Answer 37

Testosterone must be reduced to its active derivatives, such as DHT The derivatives then diffuse into the prostate, seminal vesicles, epididymis and skin Testosterone is converted by 5 alpha reductase to DHT

Question 38

Androgens Therapeutic Uses

Answer 38

Used for males with primary hypogonadism or secondary hypogonadism [due to failure of the hypothalamus or pituitary] Anabolic steroids can be used to treat chronic wasting associated with HIV or cancer Unapproved uses—increased lean body mass, muscle strength and endurance in athletes; DHEA has been touted as an antiaging hormone Danazol, a weak androgen, used to treat endometriosis and fibrocystic breast disease

Question 39

Androgens ADEs

Answer 39

Weight gain Decreased breast size Deepening voice Increased libido Increased hair growth

Question 40

Pharmacokinetic Testosterone

Answer 40

Ineffective orally C17 esters of testosterone are given IM Transdermal patches, topical gels and buccal tablets are available

Question 41

Pharmacokinetics Testosterone Derivatives

Answer 41

Alkylation of the 17 alpha position of testosterone allows oral administration -Fluoxymesterone [Androxy] hypogonadism or metastatic breast cancer in the male -Oxandrolone [Oxandrin]—orally active testosterone derivative with anabolic activity 3-13 times that of testosterone; used for weight gain in those with HIV or catabolic states; used for osteoporosis related bone pain

Question 42

Androgens Adverse Effects

Answer 42

In females—masculization, acne, growth of facial hair, deepening of voice, male pattern baldness, excess muscle development, menstrual irregularities -Pregnant women should NOT use because of possible virilization of the female fetus In males—priapism, impotence, decreased sperm production, gynecomastia, cosmetic changes [like those seen in women], stimulate growth of the prostate In children—abnormal sexual maturation and growth disturbances from premature closing of epiphyseal plates General effects—increased LDL, decreased HDL, fluid retention, edema

Question 43

Androgens Adverse Effects

Answer 43

In athletes—using anabolic steroids can cause premature closing of epiphyses of the long bones—which will stunt the growth and interrupt development High doses may result in reduction of testicular volume, hepatic abnormalities, increased aggression, major mood disorders

Question 44

Antiandrogens

Answer 44

Antiandrogens counter male hormonal action by interfering with the synthesis of androgens or by blocking their receptors Finasteride [Proscar] and Dutasteride [Avodart] inhibit 5 alpha reductase resulting in decreased formation of DHT—both are used to treat BPH Flutamide [Eulexin], Bicalutamide [Casodex], Enzalutamide [Xtandi], Nilutamide [Nilandron] act as competitive inhibitors of androgens at the target cell and taken orally for the treatment of prostate cancer

Question 45

Writing Prescriptions for Estrogens, Progestins, Androgens COCs

Answer 45

In the US, most COCs contain ethinyl estradiol [one contains estradiol valerate] Estrogens regulate endometrial proliferation and prevent ovulation and prevent estrogen deficiency induced by progestin (important) 9 different progestins used in COCs in the US—they are the main contraceptive component in COCs—they suppress LH, FSH and cause the endometrium to be unfavorable for implantation

Question 46

Progestins

Answer 46

1st Generation -Norethindrone -Norethindrone Acetate 2nd Generation -Levonorgestrel -Norgestrel 3rd Generation -Destrogestrel -Norgestimate Others -Drospirenone -Dienogest **First choice for a woman starting COCs should be a monophasic product, preferably with a 2nd generation progestin; cycle control may be better for some women with COCs containing 30-35 mcg ethinyl estradiol

Question 47

Other Scenarios where COCs Can be Used

Answer 47

Regulating the menstrual cycle Reduction of heavy menstrual bleeding Management of acne Managing dysmenorrhea Managing PMS Reduce risk of ovarian, endometrial and colon cancers During perimenopause may prevent bone loss and reduce the risk of osteoporosis Products with Drospirenone—less like to have HTN, more likely to improve mood and lessen weight gain in those with PMS

Question 48

COCs Contraindications/Risk Factors

Answer 48

ACOG states that COC is contraindicated for women 35 and older who smoke Risk factors for stroke, MI and VTE are increased in patient’s that are overweight and obese

Question 49

COCs Rings/Patches/IUDs

Answer 49

Rings -NuvaRing Patches -Xulane -Ortho Evra IUDs 3 hormonal options-Levonorgestrel coated IUDs -Skyla [3 years] -Liletta [3 years] -Mirena [5 years]

Question 50

Progestin Alternatives

Answer 50

Oral Pills—35 mcg daily -Norethindrone -Many brand names—Camila, Errin, Heather, Jencycla, Jolivette, Nora-BE, Ortho Micronor, Nor-QD Injectable -Medroxyprogesterone acetate given IM every 90 days -Depo-Provera; Depo-subQ Provera 104 Subdermal -Etonogegstrel 68 mg every 3 years -Nexplanon

Question 51

Nonhormonal Contraceptive Methods

Answer 51

Vaginal spermicides [nonoxynol-9] Male condoms Female condoms Diaphragm [Rx required]—must be left in place 6° Cervical Cap [Rx required]—can be left in place 48° Sponge—must be left in place 6° Para-Guard Copper T380A IUD [RX required]

Question 52

Emergency Contraception 3 FDA approved options for EC

Answer 52

Progestin orally in high dose, progestin receptor modulator & Copper IUD Paraguard High dose estrogen/progestin combinations also can be used, but are not FDA approved—have more S/E and are not as effective as the FDA approved methods Progestin only options are OTC and are approved for use up to 72 hours after unprotected intercourse—Plan B, One-Step, Next Choice, One Dose, My Way -Contain 1.5 mg of Levonorgestrol

Question 53

Emergency Contraception

Answer 53

Prescription options include insertion of a copper IUD—it can be inserted up to 5 days after the unprotected intercourse [will then give long term contraception for 7 years] Other option is Ulipristal [Ella]—nearly 3 times more effective than the OTC options, can be used up to 120 hours after the unprotected intercourse episode -Requires a prescription Oral forms of EC ARE affected by weight—OTC options successfully in women up to 154 pounds; Ella effective in women up tot 194 pounds

Question 54

Drugs to Manage Menopausal Symptoms

Answer 54

Bazedoxifene/Conjugated Estrogens [DuaVee] 20 mg of Bazedoxifene + .45 mg of conjugated estrogen -SERM in combination with estrogen for treating moderate to severe vasomotor symptoms associated with menopause in women with a uterus -Bazedoxifene acts as an antagonist for estrogen receptors in uterine tissue, so when given in combination with estrogen it opposes the effects of estrogens on the uterus -Bazedoxifene [Viviant] is also approved for preventing postmenopausal osteoporosis in women with a uterus Side Effects—muscle spasms, diarrhea,, nausea, indigestion, upper abdominal pain [all >10%]

Question 55

Drugs to Treat Menopausal Symptoms Bioidentical Hormone Therapy

Answer 55

Hormone based medications that are compounded by specialty pharmacies FDA does not recognize this term nor does it approve these hormones for use Formulas are inconsistent Not evidenced based

Question 56

Nonhormonal Options

Answer 56

SSRIs & SNRIs—Paroxetine 7.5 mg daily [Brisdelle] is only nonhormonal FDA approved med for the treatment of menopausal vasomotor symptoms Clonidine/Gabapentin—neither is FDA approved for vasomotor symptoms -Clonidine—centrally acting alpha agonist thought to HC elevate threshold at which the body will develop flushing—perhaps decreasing number of hot flashes; 0.05-.15 mg BID -Gabapentin—anticonvulsant, helps to manage hot flashes through an unknown mechanism; 900 mg daily

Question 57

Drugs to Treat Menopausal Symptoms Phytoestrogens and Black Cohosh

Answer 57

Phytoestrogens are plant based estrogens—alternative treatments despite a LACK of evidence supporting their use; Isoflavones [one type of phytoestrogens] are derived from soy or red clover extract—not EB

Question 58

Drugs to Treat Vaginal Symptoms

Answer 58

Lack of estrogen leads to atrophy of the vaginal tissues Before menopause, estrogen stimulated exfoliation of the vaginal cells; as the cells exfoliate, glycogen is released, which is hydrolyzed into glucose Lactobacilli in the vaginal tissues convert this glucose to lactic acid, which maintains the vaginal pH at 3.5-4.5; without estrogens, the pH increases to 5-7.5, leading to symptoms that may include dryness, discomfort itching, burning, discharge and painful intercourse Estrogens are the main treatment of vaginal symptoms—four local estrogens are FDA approved—2 creams, one ring and one tablet

Question 59

Drugs to Treat Vaginal Symptoms Ospemifene

Answer 59

Osphena is FDA approved Oral estrogen receptor agonist/antagonist, for the treatment of moderate to severe dyspareunia 60 mg daily PO with food No dosage adjustments for renal impairment or hepatic disease Fluconazole and Rifampin cannot be taken while on Osphenia Side effects—hot flashes, vaginal discharge, muscle spasms and hyperhidrosis

Question 60

Drugs to Treat Vaginal Symptoms Vaginal Options

Answer 60

Lubricants—can relieve sx of dyspareunia—use immediately before intercourse -Water based or silicone based -Yes, Astro-Glide, Replens Moisturizers—should be used routinely; at least every 3-4 days -Replens moisturizer, Luvena, KY moisturizer Women should be encouraged to continue sexual activity—helps maintain active blood flow to the vagina, which can help with lubrication and prevent atrophy

Question 61

Drugs to Manage Infections of the Genitourinary System Bacterial Etiologies

Answer 61

Chancroid Haemophillius ducreyi Zithromax 1 gram PO; Rocephin 250 mg IM

Question 62

Bacterial Etiologies

Answer 62

Chlamydia Chlamydia trachomatis Zithromax 1 gram PO; Doxycycline 100 mg BID x 7 days

Question 63

Bacterial Etiologies

Answer 63

Donovanosis Granuloma inguinale Calymmatobacterium granulomatis Zithromax 1 gram PO x 2 1 days; Doxycycline 100 mg BID x 21days

Question 64

Bacterial Etiologies

Answer 64

Gonorrhea Neisseria gonorrhoeae Rocephin 250 m g IM + Zithromax 1 gram PO Suprax 400 mg PO + Zithromax 1 gram PO

Question 65

Bacterial Etiologies

Answer 65

Lymphogranuloma venereum Chlamydia trachomatis [serotypes L1, L2, L3] Zithromax 1 gram PO; Doxycycline 100 mg BID x 7 days

Question 66

Bacterial Etiologies

Answer 66

Nongonococcal urethritis Ureaplasma urealytium Mycoplasma hominis Zithromax 1 gram or Doxycycline 100 mg BID for 7 days OR Clindamycin 450 mg q 6° for 7days Levaquin 500 mg for 7 days Ofloxacin 300 mg BID for 7 days

Question 67

Bacterial Etiologies

Answer 67

Syphilis Treponema pallidum Aq. Penicillin G 2.4 million units IM Doxycycline 100 mg BID for 14 days [both +/- Prednisone 40-60 mg daily for 3 days]

Question 68

Bacterial Etiologies

Answer 68

Bacterial vaginosis Gardenerella vaginalis Mobiluncus species Flagyl 500 mg PO BID x 7 days Flagyl gel 5 g. vaginally @ HS x 5d

Question 69

Viral Etiologies

Answer 69

CMV Cytomegalovirus Reassurance If treatment indicated—Foscarnet or Cidofovir [with ID consultation]

Question 70

Viral Etiologies

Answer 70

HSV Herpes simplex Acyclovir 400 mg TID for 7-10 days or 200 mg 5 times/day for 7-10 days Valcyclovir 1000 mg BID for 7-10 days Famcyclovir 250 mg TID for 7-10 days

Question 71

Viral Etiologies

Answer 71

HPV Human papilloma Podofilox 0.5% BID for 3 days [can repeat each week for 4 cycles] Imiquimod 5% TIW @ HS for 16 weeks Sinecatechins [Veregen] 15% ointment TID for 16 weeks Local therapies may be indicated

Question 72

Viral Etiologies

Answer 72

Molluscum contagiosum Pox virus Curettage/Cryo +/- Cantharidin [derm specialist only] Glycolic acid topically Imiquimod 5% daily [leave on 6-10°] Tretinoin topical [0.1% cream or 0.025% gel] @ HS Salicylic acid [50-80% compounded] K+ hydroxide topical [compounded]

Question 73

Protozoal Etiologies

Answer 73

Trichomonas Trichomonas vaginalis Flagyl 2 grams PO or Tinidazole 2 grams PO with food