302 final (estrogen, transitioning, etc.)

main sex hormones produced by gonads

estrogen, progesterone, androgen

• for reproductive development, secondary sexual characteristics, prepare/maintain pregnancy, menses regulation

therapeutic uses

• contraception/pregnancy support

• management of menopausal symptoms

• replacement therapy in hormone deficiency

cholesterol is major precursor for sex hormones

• progesterone can make testosterone and estradiol

• testosterone can also be synthesized into estradiol

estrogens

• primarily sourced from ovaries, binds to steroid hormone receptors (dimers), resulting in interactions w regulatory DNA sequence, allowing for transcription of targeted genes

natural estrogens

• estradiol (E2) - reproductive years - rapidly metabolized when taken orally, but still effective

  • absorbed through portal vein from GI into liver, where it is metabolized into estriol —> estrone —> excreted

  • formulations include patches, creams, spray, vaginal inserts, tablets

• estrone (E1) - menopause

• estriol (E3) -pregnancy

• *these are readily absorbed through GI tract, skin, and mucous membranes

synthetic estrogens

• ehtinyl estradiol (EE) - synthetic analog of estradiol

• mestranol - prodrug of EE

• conjugated estrogens - premarin

• estradiol valerate - estradiol prodrug

• *synthetic estrogens are more potent than natural estradiol absorbed well orally, and have prolonged duration of action

potency of estrogens least to greatest

• estriol, estrone, estradiol, estradil valerate, conjugated estrogens, mestranol, ethinyl estradiol

estrogen for postmenopausal hormone therapy

• symptoms include: vasomotor (hot flashes, night sweats), genitourinary (vaginal changes w dryness, thinning and spotting, or bladder/urethra changes w painful urination and urgency/frequency), bone loss and fracture risk, mood/sleep disturbances

• treatment of choice: oral conjugated equine estrogens (premarin)

  • or transdermal and intravaginal estradiol

• if pt has no uterus: estrogen therapy ONLY

• if pt has uterus: estrogen AND progesterone therapy (progesterone helps prevent thickening of uterine lining which is influenced by estrogen —> inc thickening can lead to cancer)

estrogen for contraception

typ estrogen and progesterone combination

estrogen therapy increases risk of

thromboembolism (clots), CV events (HTN, fluid retention, heart attack, stroke), endometrial hyperplasia/cancer, breast cancer, vomiting, GI, breast discomfort, etc.

SERMs

• selective estrogen receptor agonists (agonize some tissues and antagonize others)

• used for prevention/treatment of breast cancer, osteoporosis, treatment of menopausal symptoms and infertility

drugs:

• tamoxifen

• raloxifene

• bazedoxifene

• clomiphene

tamoxifen

• estrogen receptor inhibitor in the breast (regression of breast tumors)

• ER agonist in uterus and bone (decreased bone loss, but inc risk of endometrial cancer)

• for treatment and prevention of breast cancer

• AE: hot flashes, night sweats, vaginal dryness, inc lipids, inc risk of clotting and endometrial cancer

raloxifene

• antagonist in breast and agonist in bone

• NO agonistic effect on uterus (no inc risk of endometrial cancer)

• only for high risk pt breast cancer prevention

• only SERM approved for treatment and prevention of osteoporosis in postmenopausal pt

• AE: hot flashes, inc clot risk in legs or lungs

bazedoxifene

• ER inhibitor in uterus and breast (dec risk of endometrial cancer + breast cancer)

• ER agonist in bone (dec bone loss)

• used for relief of menopausal vasomotor symptoms and osteoporosis prevention

• AE: low SE profile, amenorrhea, breast tenderness

clomiphene

• ER antagonist in hypothalamus and uterus

  • in hypothalamus, blocks negative feedback of estradiol, increasing secretion of ovulation stimulating hormones

• common for fertility treatments to induce ovulation

• AE: hot flashes, headache, mood, disturbance, inc risk of multiple gestation

progesterone

• produced in response to LH and stimulates secretion of matureuterine epithelium, preparing it for embryo implantation

• used for contraception + HRT and often used in combination w estrogens

• natural progesterone: not used for contraceptive therapy bc rapid metabolism (low bioavailability)

• treatment of menstrual disorders, menopausal hormone therapy, endometriosis, infertility

synthetic progesterone (progestins)

order of androgenic acitvity (least to greatest): 4th gen, 3rd gen, 1st gen, 2nd gen

estrogenic activity: 1st and 3rd gen have more estrogenic activity, 2nd and 4th gen have less estrogenic activity

• more stable for oral admin and have a half life of up to 30 hrs (once dialy dosing)

• AE:

  • progestin related: depression, inc appetite (weight gain), dec libido, fatigue, amenorrhea, fatigue

  • estrogen related: headache, nausea, inc. bP, fluid retention

  • androgen realted: acne, hirsutism (inc hair growth in women)

medroxyprogesterone acetate

injectible contraceptive w effects for about 3 months

antiprogestins

• mifepristone:

  • progesterone antagonist —> cessation and termination of pregnancy

• misoprostol:

  • often combined w mifepristone, results in softening of cervix and induces uterine contractions

  • AE: abdominal pain, uterine bleeding, nausea, diarrhea, fatigue

types of contraceptives + most effecti e

hormonal, sterilization, nonhormonal

hormonal and sterilization are more effective

COCs (combined oral contraceptives)

• combination of EE and progestin

• MOA:

  • estrogen: prevents ovulation by suppressing FSH

  • progestin: helps thicken cervical mucus and causes atrophy of endometrial lining

• most common type of oral contraceptive

• initiate medication via two diff methods

  • first day method (take 1st active tablet first day of menses —> no backup contraception required

  • quick-start method (take 1st active tablet regardless of menses w backup contraception for first 7 days after starting)

• typically you have active pills (21-24) followed by placebo pills (4-7 days)

• monophasic: active pills have constant dose of estrogen and progestin

• multiphasic: active pills have constant dose of estrogen w inc doses of progestin to mimic natural female cycle (dosage changes 4+ time through cycle) (ie. biphasic v triphasic)

missed dose of coc

• 1 hormonal pill is late (less than 24 hrs since it should have been taken or missed (24-48 hrs since)

  • take pill asap and continue pills at same time

  • type doesn’t require emergency contraception

• 2+ consecutive pills are missed (>=48 hrs since missed)

  • take most recent missed pill asap AND discard other missed pill

  • continue but abstain from sex/use brarrier methods until taken for 7 days consecutively

  • if you missed them in the last week of hormonal pills, skip placebo and finish hormonal pills, starting new pack next day —> if unable then abstain and consider EC

different types of COCs

• extended cycle contraceptive

  • placebo interval —> withdrawal bleeding

  • 84 pills followed by 7 dyas of placebo to decrease frequency of withdrawal bleeding

• continuous oral contraceptive - active pills only

  • usually indicated for endometriosis, premenstrual dysphoric disorder, polycystic ovary syndrome, lifestyle reasons

• transdermal patch xulane

• vaginal ring

transdermal patch xulane

• ethinyl estradiol and norelgestromin

• apply patch once a week at beginning of cycle for 3 weeks followed by patch free week (to upper arm, shoulder, buttock)

• change patch same day each week and rotate application site to prevent irritation

• inc exposure to estrogen relative to oral contraceptives

• safety/efficacy can be effected by body weight (ESP if BMI > 30) and less effective in pt > 90 kg

• firstday/quick start method if no prior CHC

  • if switching from another CHC, apply patch on first day of withdrawal bleeding and no backup is required

transdermal patch xulane delayed application

• <48 hrs since: apply new patch ASAP (if patch was detached, try to reapply/replace)

  • keep same patch change day

  • no additinoal contraceptives, usually dont need EC but consider if delayed application earlier/during last week of previous cycle

• >=48 hours since: apply new patch ASAP

  • keep same patch change day

  • abstain from sex/use barrier methods until patch is worn 7 days consecutively

  • if during 3rd patch week, omit hormone free week

  • consider EC if detached in first week of use and unprotected sex in previous 5 days

vaginal ring

• ethinyl estradiol and etonogestrel

• inserted into vagina for 3 weeks then rign free week w similar safety/efficacy to COCs

• delivers hormones through vaginal mucosa via nonbiodegradable rings

• ring can be left in place during sex, tampon, topical cream

• don’t use diaphragm, or in patients prone to vaginal irritation/dont want insertion

• initiation: insert on/before 5th day of menses same time and day each week

delayed vaginal ring

• delay placement for <48 hrs

  • place in ASAP until scheduled removal day

  • no additional contraceptive require, but consider if ddelayed placement occurs earllier in the cycle/last week of previous cycle

• delayed placement >48 hrs

  • place in ASAP until ring removal day and abstain until ring has been used for 7 days consecutively

  • if ring removed during third week, omit hormone free week and start new ring after finishing OR abstain until ring has been used 7 days consecutively

  • same stuff as before w 5 days and whatever

CI for combined hormonal contraception (category 4)

• breastfeeding and <21 days postpartum

• smoker >35

• risk factor for CVD, current/history of blood clots

• BP>160/100

• major surgery w immobilizaiton

• breast cancer

• migraine headache w aura

• common AE: breakthrough bleeding early or late cycle —> fix by inc estrogen early cycle and inc progestin late cycle

  • weight gain (noncyclic v cyclic

    • noncyclic: dec progestin

    • cyclic: dec estrogen

  • headaches —> dec estrogen and have a shorter placebo/extended cycle

  • acne —> dec progestin and use 3rd/4th gen progestin like drospirenone

POPs

• progestin only pills, usually w norethindrone or norgestrel

• no estrogenic SE and no hormone free week

• indicated for pt w CI to estrogen drugs/breastfeeding

  • these include migraine/headache, breastfeeding, severe liver disease, high risk/history for VTE, hx, high CV risk, 35+ active smoking

• MOA suppress GnRH, LH, FSH

  • norethindrone may not suppress ovulation, but can help thicken cervical mucus, causing endometrial lining to atrophy

• OTC PILL: OPILL (norgestrel)

• no placebo pills

• RISK of unintended pregnancy if weight >60kg

• taken same time each day via first day method/quick start method (backup for 1st 48 hrs)

missed dose of norethindrone/norgestrel POPs

• (>3 hrs since taken)

  • take ASAP, continue pills daily at same time (Even if you ahve to take 2 a day)

  • abstain from sex/use barrier until pills used 2 days consecutively

  • EC if unprotected sex

drospirenone POPs missed dose

• <48 hrs since

  • take ASAP, continue taking pill a day and dw abotu additional contraceptive

• >=48 hrs since: take last missed pill asap and continue until finished pack

  • abstain until pills taken for 7 consecutive days

  • EC if pills missed during first week and sex during prev 5 days

progestin injections/implants

• medroxyprogesterone acetate (DMPA)

• etonogestrel implant (nexplanon)

• progestin intrauterine device (IUD) w levonogestrel

medroxyprogesterone acetate (DMPA)

• IM/SQ admin every 3 months (depo refers to storage in muscles)

• MOA: prevents ovulation by suppressing GnRH, LH, FSH, and thickens cervical mucus

• no dose adjustment for BMI

• AE: osteoporosis risk, amenorrhea, weight gain, stopped period

• return to fertility after discontinuation may be delayed for several months

• not recommended to use for longer than 2 yrs bc bone density risk

• initiate within 5 days of start of menses (no backup required)

  • if >7 days since start, then use backup for 7 days

  • subsequent doses: every 3 months w 2 week grace period for delays in dosing

etonogestrel implant (nexplanon)

• long acting reversible contraceptive (LARC)

• MOA: sustained release of progestin which suppresses release of LH and prevents ovulation

• subdermal implant in upper arm removed after 3 yrs

• AE: irregular menstrual bleeding, amenorrhea, weight gain

progestin intrauterine devise (IUD) w levonogestrel

• LARC (works 3-8 hyrs and improves dysfunctional/heavy bleeding)

• MOA: prevents implantation and disrupts endometrial lining

  • locally thickens cervical mucus and inhibits sperm motility

• some are used as EC

• AE: amenorrhea, spotting

• CI: pt w pelvic inflammatory disease

• *pain upon insertion, initial bleeding/spotting, reduced menstrual bleed overall

• *Copper IUDs are nonhormonal and work up to 10 yrs

  • release copper ions into uterus and creates toxic environment for sperm

  • also effective if taken w/in 5 days of unprotected sex and can be used as contraceptive for up to 10 years

emergency contraception

• *dec efficacy in BMI > 25

• levonorgestrel EC

• ulipristal (ella)

levonorgestrel EC

• single high dose progestin

• slows release of GnRH —> suppresses LH surge —> delays/inhibits ovulation

• use within 72 hrs of unprotected sex and available OTC

• dec efficacy if BMI > 26

ulipristal (ella)

• selective progesterone modulator: binds to progesterone receptors —> delays ovulation, dec endometrial thickness

• use within 120 hrs and prescription only

androgens

• inc masculine characteristics and can be used anabolically for muscle building

• used for sperm production, muscle protein synthesis, male maturation, dec bone resorption (helps w bone buildup)

• testosterone: synthesized in testes and in smaller amnts in the ovaries and adrenal glands

  • production regulated by HPG axis (hypothalamus releases GnRH to anterior pituitary, which releases LH and FSH to testes which produce testosterone

  • can actively bind to muscles and liver

• DHT

  • active metabolite of testosterone

  • needed to bind to other tissue (skin, prostate)

androgen uses

• primary, secondary hypogonadism; muscle wasting disorders (HIV/AIDS, cancer, burns), endometriosis/fibrocystic breast disease, masculinization

• contraversially used for androgen deficiency in aging (to inc libido), improving athletic performance, and prevention of osteoporosis in elderly males

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testosterone

• not effective orally w a 1:1. androgenic:anabolic ratio

• patch, gel/solution, buccal tablet, implant

• testosterone esters —> esterified testosterone (lipid soluble) inc duration of actiona nd administered IM q 2-4 weeks

• AE: acne, facial hair, deepening of voice, balding (inc. DHT), amenorrhea, excess muscle development

  • inc. lipids + risk of heart/liver damage

  • inc androgen —> priapism, breast development, inc prostate growth, mood swings, aggression, shrunken testicles, and infertility

  • in children: abnormal sexual maturation and growth disturbances

methyltestosterone and fluoxymesterone

• testosterone derivatives

• 17-alkyl substituted androgens —> less hepatic metabolism and allows for oral admin

• 1:4 androgenic:anabolic activity

• AE: inc hepatic toxicity and cancer (bc inc liver enzyme levels) relative to testosterone

antiandrogens

• androgen receptor antagonists (directly inhibit androgen)

  • indicated to treat prostate cancer

• 5-alpha reductase inhibitors —> block conversion of testosterone to DHT

  • finasteride and dutasteride for benign prostatic hyperplasia and alopecia

menstrual cycle

day 1: first day of period

day ~14: ovulation

days 0-14: follicular phase

days 15-28: luteal phase

US MEC (medical egilibility criteria) risk categories

1 is no restriction, 4 is unacceptable health risk

DSM criteria for gender dysphoria

include at least 2 of various gender dysphoria markers and B) the conditions are associated w clinically significant distress/social/occupational impairement

condition can be diagnosed w

• condition existing w disorder of sex development

• post transitional condition

criteria for hormone therapy for adults

1) persistent, well-documented dysphoria/incongruence

2) capacity to make fully informed decisions and to consent to treatment

3) age of majority

4) mental health concerns are reasonable controlled

puberty blockers

• delays onset of puberty and allows time for further assessment

• alleviates anxiety/depression w gender dysphoria, opportunity for social transition w/out permanent physical changes

• gender affirming hormones initiated later in adolescence

• GnRH analogues - leuprolide acetate and triptorelin (two separate injectibles)

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leuprolide acetate and triptorelin

• GnRH analogue puberty blocker

• MOA: initial stimulation followed by desensitization of GnRH receptors in pituitary → dec secretion of LH and FSH → dec production of sex steroids (testosterone and estrogen) from gonads

• AE: hot flashes, fatigue, mood alterations

  • reversible bone mineralization (hardened bone + inc ca in bone)

  • compromised fertility (esp if treated w sex hormones afterwards)

  • unknown effects on brain development

• CI:

  • pregnancy and lactation (can harm fetus)

  • undiagnosed/abnormal vaginal bleeding

  • uncontrolled, severe psychiatric disorders

feminizing gender affirming HT

• general approach estrogen + androgen blocker

• gen MOA: E2 binds to extranuclear estrogen receptor which activates secondary messengers (GPCR protein) and alters transcriptional effects

• E2 also binds to her/hrb heterodimer inside cell and acts more directly on DNA/transcription

• drug of choice: 17BETA-ESTRADIOL (estradiol product)

  • injections, patches, tablets

• other drugs:

  • conjugated estrogens

  • ethinyl estradiol

conjugated estrogens for feminizing HT

• inability to accurately measure blood levels

• potential increased risk for thrombotic/CV

ethinyl estradiol for feminizing HT

inc risk for TE

route of admin for estrogen products for feminization therapy

• injection:

  • fast onset, not subject to first pass liver metabolism

  • issues w injection site rxns, cyclical fluctuations in hormones

• patch

  • not subject to first pass liver metabolism, preferred in pt w inc TE risk

  • issues w skin irritation, patch adhesion, multiple patches may be required

• tablet

  • simple to adjust dosing/monitor levels

  • metabolized during first pass liver metabolism

estrogen products for feminizing therapy

• MOA: development and maintenance of female reproductive system and secondary sexual characteristics

• AE: hot flashes, mood swings, elevated TG

• CI: VTE related to underlying hypercoagulable state, end-stage liver disease, and estrogen sensitive neoplasm (cancer)

• monitoring:

  • goal estradiol: 100-200

  • goal testosterone: <50

  • lipid panel

• estrogen CV system increases blood clotting and vasodilation

spironolactone

• androgen blocker

• MOA: competes w DHT and testosterone for androgen receptors

• AE: nocturia (pissing at night), hyperkalemia, orthostasis, gynecomastia

• CI: hyperkalemia, addison’s disease

• monitor: k levels and renal function

the development of which female secondary sex characteristics is irreversible

• breast growth onset 3-6 months and reaches max at 2-3 years

• suppression of testicular volume (within 3-6 months max at 2-3 yrs)

• suppression of sperm production (max at greater than 3 years)

• AE: include decreased sexual desire, male sexual dysfunction, skin oiliness/acne

masculinization

• testosterone enters cell as DHT and binds to AR dimers to target genes in nucleus

• drug of choice: testosterone cypionate

  • other drugs include: testosterone enanthate, testosterone propionate

• MOA: endogenous androgen resonsible for promoting growth/development of male sex organs and maintaining secondary sex characteristics

• AE: polycythemia (high RBC), weight, mood lability, infertility, inc. sex drive, lower HDL cholesterol

• CI: breast cancer, prostate cancer, pregnancy

• monitoring:

  • goal testosterone at 500-700

  • goal estradiol at <50

  • CBC (hgb/hct), liver function tests, lipid panel

• effects of testosterone

  • improves cardiac contraction/output and improves affect on cardiomyocytes, inc heart and shit

  • sebum production, balding, etc.

  • inc libido and shit

administration of testosterone

• IM/SQ (sq preferred over IM

• patch

  • risk of skin irritation

• gel

  • favorable choice for those w underlying mental health conditions

  • risk of unintentional exposure to another person

irreversible effects on testosterone

• irreversible male secondary sex characteristic development

  • facial/body hair growth (onset 6-12 mo and peaks at 4-5 yrs)

  • deepening of voice (onset 6-12 mo and peaks at 1-2 yrs)

• irreversible femae secondary sex characteristic suppression

  • clitoral enlargment (onset 1-5 mo and peaks at 1-2 yrs)

GAHT planning

• * all GAHT are off label

• managing expectations (takes time, psychological changes occur sooner than physical, monitor dose/levels and titrate as needed, full effects may take months - years

• emotional changes: emotional lability is common w testosterone (inc anger/irritability)

  • lots of symptoms → evaluate hormoen levels and admin method

  • psychotherapy can benefit during transition

• fertility options - should be counseled before medical/surgical transition

  • HT effects - can impair but not always eliminate fertility

    • discontinuation can lead to return of ovulation/spermatogenesis, but some may experience permanent loss

  • hormones are not reliable contraception

  • testosterone is teratogenic

• reproductive options: may require assisted reproductive technologies (ART)

• long term hormone exposure risks to gametes/offspring are unknown

• trans women fertility options

  • estrogen may damage testes → cryopreservation of sperm prior to initiation

• trans men fertility options

  • fertility may return after stopping therapy

  • fertility preservation options include oocyte cryopreservation, embryo cryopreservation, ovarian tissue cryopreservation