PHAR 7341 B3 Endocrine

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Contraceptives Government & Law Right to refuse

"A pharmacy's or pharmacist's refusal to sell birth control does not violate a woman's federal constitutional rights. The U.S. Constitution imposes no limitations on nongovernmental institutions like privately owned pharmacies. Even if the refusal takes place in a state-owned pharmacy, a woman has no federal constitutional right to receive contraception. Although the Constitution protects a woman's right to contraception, it does not ensure that women can access reproductive health services." -American Civil Liberties Union (ACLU)

Other hormonal contraceptives Transdermal contraceptives ADRs

*Higher than OCs due to 60% higher exposure to estrogen than OCs containing 35 mcg EE

Benign Prostatic Hyperplasia AUA Guidelines: BPH

*If indicated, phosphodiesterase inhibitors should be used cautiously with concomitant α-adrenergic antagonists (alpha-1 blockers). PDEI can enhance hypotensive effects of alpha-1 blockers.

Oral contraceptives Androgen excess

- more common in 1st & 2nd generation progestins

Prostaglandin E1 (Alprostadil) Alprostadil Injection (Caverject®, Edex®) Pharmacological Effect

-- Activates EP prostaglandin receptor -- Activates adenylyl cyclase & increase cAMP -- Decreases Ca influx in cavernosal arterial & trabecular smooth muscles -- Relaxation of both smooth muscles -- Erection

Oral contraceptives Drug interactions Antiepileptics

-- Best documented culprits: phenobarbital, carbamazepine, phenytoin -- Lamotrigine effectiveness is decreased by OCs and OC effectiveness may be decreased slightly my lamotrigine -- Other anticonvulsants may also interact -- Women should be offered another form of contraception -- Depot medroxyprogesterone or IUDs are preferred o Risk of OC failure highest with low dose formulations o Management -- Abstain from intercourse -- Use additional method of contraception -- ? Higher dose OCs

PCOS Associated Morbidity and Evaluation

-- Cutaneous manifestations -- Infertility -- Pregnancy complications -- Endometrial cancer -- Obesity -- Depression -- Sleep-disordered breathing/obstructive sleep apnea (OSA) -- Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) -- Type 2 diabetes mellitus -- Cardiovascular risk

Prostaglandin E1 (Alprostadil) Alprostadil Injection (Caverject®, Edex®) Therapeutic Use:

-- Erectile dysfunction -- diagnostic tests for erectile function

Contraceptives Pharmacology Estrogens - Pharmacodynamics Metabolism

-- Natural estrogens: T½ = 3 h; first pass metabolism -- Ethinyl estradiol (T½ = 36 h), mestranol (T½ = 9-24 h); liver metabolism (cytochrome P450), excreted in bile, re-absorbed in gut

PDE5i Long-term efficacy

-- No evidence for tachyphylaxis -- Continues to be effective with long-term use

Contraceptives Pharmacology Progestins - Pharmacokinetics Routes of administration

-- Oral -- Parenteral - IM -- Local - vaginal gel/insert, intrauterine device

Prostaglandin E1 (Alprostadil) Alprostadil Injection (Caverject®, Edex®) Adverse effects

-- Penile pain (37%) -- Prolonged erection (4%) -- Penile fibrosis (3%) -- Injection site hematoma (3%)

Concerns of all IUDs

-- Uterine perforation during insertion -- Inadvertent expulsion -- Introduction of bacteria into uterus -- (No increased risk of infection after 1 month)

Unintended pregnancy o Consequences for fetus:

--- Women less likely to seek early prenatal care or prenatal care at any time --- Fetus is more likely to be exposed to harmful substances --- Child is more likely to weigh less than 5.5 pounds at birth --- Child is more likely to die in first year of life, be abused, and/or receive insufficient resources for healthy development

Infertility Epidemiology

1 in 8 couples (12% married women) have trouble getting pregnant or sustaining pregnancy Approximately 1/3 of infertility is attributed to the female partner, 1/3 attributed to the male partner and 1/3 is caused by a combination of problems in both partners or, is unexplained In approximately 40% of infertile couples, the male partner is either the sole cause or a contributing cause of infertility 85%-90% of infertile couples are treated with conventional medical therapies

Benign Prostatic Hyperplasia Normal Prostate Physiology Pathophysiology Summary

1. Anatomic enlargement of prostate gland 2. Excessive α-adrenergic tone of stromal tissue o Stromal: Epithelial Ratio -- Normal prostate - 2:1 -- BPH - 5:1

Benign Prostatic Hyperplasia Overall and Specific Goals of Treatment

1. Control symptoms -- Improvement of AUA Symptom Score by at least 3 points -- Increase in peak urinary flow rate -- Normalization of PVR < 50 mL 2. Prevent progression of complications 3. Delay need for surgical intervention

Menstrual Cycle

1. Hypothalamus releases GnRH and pituitary releases FSH/LH 2. FSH/LH stimulates follicle growth 3. Proliferative phase -- Follicle growth increase in estradiol 4. LH surge triggers ovulation: follicle rupture, release 2º oocyte 5. Follicle turns into corpus luteum 6. Increase progesterone and estradiol 7. Stimulate thickening of endometrium for fertilization 8. No fertilization= endometrium breakdown

Benign Prostatic Hyperplasia Evaluation of Therapeutic Outcomes

1. Improvement of voiding symptoms with minimal treatment-related adverse effects -- AUA Symptom Score 2. Urinary flow rate 3. PVR urine volume 4. PSA (annually) -- 5α-reductase inhibitors - second PSA taken after 6 months and compare to baseline measurements 5. Digital rectal examination (annually) 6. Renal function (BUN, SCr)

Benign Prostatic Hyperplasia General Approach to Pharmacologic Treatment

1. Relax prostatic smooth muscle (α-antagonists and phosphodiesterase inhibitors) 2. Decrease testosterone stimulatory effect (5α-reductase inhibitors) 3. Relax bladder detrusor muscle (anticholinergic agents)

Medications Associated with Female Sexual Dysfunction

Amphetamines Anticholingerics Antihistamines Cardiovascular and antihypertensives Hormonal preparations Trazodone Venlafaxine Narcotics Psychotropics (SSRIs, benzodiazepines, etc)

Monitoring for all hormonal contraceptives

Annual blood pressure monitoring Well Women exams Assess for ADRs STI testing when indicated

Oral contraceptives Drug interactions o OC effectiveness can be limited by drug interactions -- Decreased GI absorption -- Increased intestinal motility due to gut flora alterations -- Altered metabolism, excretion, or binding

Antibiotics o Rifampin - well-documented interaction -- Use backup for 7-28 days after discontinuation o Other antibiotics -- Tetracyclines - case reports -- Penicillin derivatives - case reports -- Conservative measure: caution women

Other hormonal contraceptives Vaginal ring Missed ring exchange

As long as total insertion time ≤4 weeks no backup needed

Pelvic Inflammatory Disease

Caused from sexual transmitted infections (STIs) -- 85% of cases - STIs or bacterial vaginosis (BV) associated pathogens -- <15% of cases - enteric or respiratory pathogens Risk factor for tubal infertility -- Tubo-ovarian abscess Risk ↑ with each infection More pronounced in older women

Female Sexual Dysfunction Pathophysiology

Changes in neurotransmitters Hormonal changes (i.e. menopause) Decline in estrogen concentrations Drug-induced changes

Oral Planned Contraceptives Formulations

Combination oral contraceptives (E+P) -- Monophasic -- Biphasic -- Triphasic -- Quadraphasic -- Estrophasic -- Extended Cycle Progestin-only oral contraceptives

Oral contraceptives CHC

Combined Hormone Contraceptive

Oral contraceptives COC

Combined Oral Contraceptive

Other hormonal contraceptives Vaginal ring Ring displacement

Common during intercourse <3 hours rinse off, re-insert, no backup needed ≥3 hours insert new ring immediately, use backup for 7 days Displacement during 3rd week skip hormone-free interval and insert new ring immediately Spotting may occur

Premenstrual dysphoric disorder (PMDD) Premenstrual syndrome (PMS)

Constellation of symptoms including mild mood disturbances and physical symptoms occurring prior to menses and resolving with menses initiation

Oral contraceptives: history

Current products contain lower hormone doses than historical products

Menstrual disorders Amenorrhea

Definition: lack of menstrual bleeding

Contraception

Definition: prevention of pregnancy following sexual intercourse by: o Barriers or medications that prevent ovulation resulting in inhibiting viable sperm from coming into contact with an ovum o Creating an unfavorable uterine environment resulting in preventing a fertilized ovum for implanting successfully in the endometrium

Other hormonal contraceptives Injectable progestins

Depot medrogyprogestrone acetate (MPA): Depo-Provera®

Therapeutics of Sexual Dysfunction Etiology Risk factors

Diabetes Hypertension Dyslipidemia Smoking Medications Obesity Benign prostatic hyperplasia Hypogonadism Thyroid disorders Depression Alcohol abuse Drug abuse Age Peripheral arterial disease Vascular/prostate surgery Trauma Surgery to pelvis/spine

Oral contraceptives Contraception Product Selection All similarly effective o Choose based on: Hormonal content -- Estrogen usually = ethinyl estradiol (EE) -- Progestins vary considerably

Dose High dose, Low dose, Ultra-low dose (see below) Healthy women o ≤35 mcg of EE o ≤0.5 mg norethindrone or equivalent o Higher doses increase ADR risk o Consider even lower doses if: -- ?Adolescent -- Underweight -- Age >35 years -- Perimenopausal

Male Hormonal Regulation Present in up to 40% of cases

Due to impaired sperm production or function Impaired sperm production o Hypogonadism -- Testicular trauma -- Cryptorchidism -- Radiation -- Antiandrogen medications

Contraceptives Pharmacology Oral Planned Contraceptives

Estrogens used in Oral Contraceptives

Oral contraceptives Contraception Product Selection Formulation

Extended cycle Reduce # of periods/year by increasing # of active tablets Consider in patients with premenstrual symptoms, menstrual migraines, or dysmenorrhea Commercially available -- Combine packs of monophasics Skip placebo pills for one or several months Safe with all monophasic OCs No physiologic need for a period -- Can take continuously up to one year o Continuous -- Active pills every day

Unintended pregnancy

Healthy People 2020 Goal: reduce unintended pregnancy by 10% -- Abortion and teen pregnancy are at all-time low Without contraception, 85% of couples will have a pregnancy within 1 year

Oral contraceptives Missed tablets for POPs

If a tablet is missed or patient is more than 3 hours late taking a tablet, backup should be used for 48 hours

Oral contraceptives Routine daily administration of COCs p1

If one tablet is missed/late o Take as soon as remembered o Take rest of pack as prescribed o Typically, no backup needed If two or more is missed/late o Take one missed tablet as soon as remembered o Discard remaining missed tablets o Take rest of pack as prescribed --- Two tablets may need to be taken on the same day, e.g. one missed tablet and one regularly scheduled tablet o Use backup for 7 days

Benign Prostatic Hyperplasia α-Adrenergic Antagonists Second-generation

Immediate-release: start at low dose and slowly titrate to therapeutic dose Extended-release: can start at therapeutic dose No dose adjustments for renal impairment Lowest effective dose in hepatic impairment

Non-Oral Planned Contraceptives Subdermal implant Progestin only

Implanon® & Nexplanon® o Etonogestrel (68 mg) o Soft, flexible rod (4 cm long, 2 mm diameter) o Inserted in the inner side of upper arm o Long lasting, up to 3 years o Release rates 60-70 mcg/day @ 5-6 wk 35-45 mcg/day @ end of 1st year 30-40 mcg/day @ end of 2nd year 25-30 mcg/day @ end of 3rd year ** Nexplanon® contains barium sulfate (detectable by X-ray)

Emergency contraception Copper IUD

Insertion within 120 hours of intercourse prevents implantation

Benign Prostatic Hyperplasia Non-pharmacologic

Low-fat diet High intake of fresh fruits and vegetables Regular physical exercise No smoking

Menstrual cycle Body prepares for potential pregnancy each month by cycling through different concentrations of key hormones -- Can be characterized by changes in the follicles of the ovary (ovarian cycle) and in the endometrial lining (uterine cycle)

Menstruation: monthly shedding of the lining of the uterus o Synonyms: menses, menstrual period o Shedding/sloughing of tissue and blood -- ~40 mL of blood -- ~35 mL of serous fluid & cellular debris -- Plasmin present breaks up blood clots

Symptoms of normal menstruation

Moodiness Cramps Trouble Sleeping Bloating Food Craving Acne

Therapeutics of Sexual Dysfunction Erectile Dysfunction Medications Associated with Causing or Exacerbating ED

Most common: antihypertensive and antidepressants

Hormonal contraception Premenstrual dysphoric disorder (PMDD) Pharmacologic treatment

No preferred agent; monophasics in most trials

PDE5i Pharmacokinetics

OK to take PDE5i with or near meal, but high fat meals (± 1 h), such as fries and cheeseburger, may slow down absorption except tadalafil.

Hormonal contraception Oral contraceptives: effectiveness With perfect use, 99% effective With typical use, 92% effective

Obesity o 2-4x more pregnancies/100 woman-years o Mechanisms -- Increased basal metabolic rates result in increased hepatic enzyme induction which results in decreased serum concentrations of OCs -- Hormones sequester in adipose tissue result in decreased serum concentrations o Especially problematic in low-dose OCs o Do not use transdermal patch first line if >90 kg o ACOG recommends POPs due to increased risk of VTE in obesity

Benign Prostatic Hyperplasia Epidemiology

Occurs in 80% of older adult men Peak onset 63-65 years of age

Routes of administration Contraceptives Pharmacology Estrogens - Pharmacodynamics

Oral Parenteral - IM Transdermal Topical - vagina or skin

Clomiphene (Clomid®) PCOS Treatment Monitor ovulation

Ovulation predictor kits, ultrasound, serum level estradiol, LH +/- progesterone

Infertility - Female Risk Factors

Ovulatory disorders Endometriosis Pelvic adhesions Tubal blockage/tubal abnormalities Hyperprolactinemia

Therapeutics of Sexual Dysfunction Erectile Dysfunction ED Definition National Institute of Health (NIH) Consensus Development Panel

Persistent failure to achieve a penile erection to allow for satisfactory sexual intercourse

Contraceptives Pharmacology Estrogens - Pharmacodynamics

Pituitary Inhibition of GnRH, FSH, & LH release, thus suppression of follicle maturation & ovulation

Hormonal control of menstrual cycle FSH

Produced: Anterior pituitary Function: o Stimulates estrogen secretion o Stimulates growth of immature ovarian follicles in the ovary

Hormonal control of menstrual cycle LH

Produced: Anterior pituitary Function: o Stimulates progesterone secretion o Triggers ovulation and development of the corpus luteum

Hormonal control of menstrual cycle GnRH

Produced: Hypothalamus Function: o Stimulates pituitary to secrete FSH and LH above basal level o Released in pulses every 2 hours with corresponding pulses in LH and FSH

Hormonal control of menstrual cycle Progesterone

Produced: Ovary (corpus luteum) Function: o Prepares the endometrium for pregnancy o Inhibits contraction of the uterus o Inhibits development of new follicle

Hormonal control of menstrual cycle Estrogen

Produced: Ovary (follicle) Function: o Develops female sex characteristics o Thickens the endometrium for pregnancy o Antagonizes PTH; increases blood clotting

Menstrual disorders Dysmenorrhea Goals of Therapy

Relieve pelvic pain Reduce missed school/work days Improve quality of life

Other hormonal contraceptives Vaginal ring Intercourse

Ring may be dislodged Most women do not report discomfort

Benign Prostatic Hyperplasia Phytotherapy

Role: mild to moderate LUTS Products are not standardized and long-term safety data unavailable Serenoa repens (saw palmetto) Pygeum africanum (tree bark) Cucurbita pepo (squash) Urtica diocia (stinging nettle)

Intrauterine insemination (IUI)

Sample inserted directly into the uterus Sperm washing highly recommended

Intracervical insemination (ICI)

Sample inserted into cervical opening

Female Sexual Dysfunction Diagnosis

Screening tools Medical, social, medication, and sexual history

Hormonal contraception Oral contraceptives: adverse events

Serious adverse events o ACHES discontinue immediately -- Abdominal pain -- Chest pain -- Headaches -- Eye problems -- Severe leg pain

Venlafaxine Premenstrual dysphoric disorder (PMDD) Pharmacologic treatment

Serotonin norepinephrine reuptake inhibitor

PHOSPHODIESTERASE INHIBITORS

Sildenafil Vardenafil Avanafil Tadalafil

Benign Prostatic Hyperplasia Clinical Presentation Irritative Symptoms (hypertrophied muscle decompensates and unable to contract sufficient force resulting in bladder ineffective in storing urine; occurs in ~50-80% patients) *Collectively, called lower urinary tract symptoms (LUTS)*

Small amounts of urine irritate bladder Urinary frequency and urgency Bedwetting or clothes wetting occurs Wakes up q1-2 hours at night to void (nocturia) KEY WORDS: frequency, urgency, nocturia

Hypogonadotropic Hypogonadism Monitoring

Testosterone levels measured every 6-8 weeks Monthly sperm count (≥ 18-24 million/mL for full restoration)

Benign Prostatic Hyperplasia Clinical Presentation Obstructive Symptoms (mechanical obstruction of urine flow caused by prostate) *Collectively, called lower urinary tract symptoms (LUTS)*

Urinary hesitancy/straining (difficult to urinate despite urge) Weak urine stream Urine dribbles out of penis Urinary bladder feels full, even after voiding Need to press on bladder to force out urine Urinary retention Start-stop pattern Suprapubic pain from bladder overdistension

Therapeutics of Sexual Dysfunction Etiology Causes

Vascular Artherosclerosis Peripheral vascular disease Hypertension Neurologic Stroke Spinal cord injury Neuropathy from diabetes Hormonal Hypogonadism Psychological Performance anxiety Depression Medications

Contraceptives Government & Law National current events

Women's March -- January, 2017 -- Long-term impact: ???

Benign Prostatic Hyperplasia α-Adrenergic Antagonists

alfuzosin doxazosin prazosin silodosin tamsulosin terazosin

Secondary infertility

at least one previous conception has been documented

Premenstrual dysphoric disorder (PMDD) PMDD

complex psychiatric disorder with multiple biologic, psychological, and sociocultural determinants

Primary infertility

conception has never taken place

Infertility

failure to conceive after 12 months of regular unprotected sexual intercourse

Benign Prostatic Hyperplasia 5α-reductase inhibitors

finasteride dutasteride

Endometriosis √ Progression

o 17-29% of lesions will resolve spontaneously o 24-64% will progress o 9-59% are stable over 12 months

Benign Prostatic Hyperplasia Normal Prostate Physiology

o 2 isoforms of 5α-reductase -- Type I: extraprostatic (skin) -- Type II: prostatic (nuclear membrane of stromal cell, not in epithelial cells) o Testosterone diffuse into cell -- Epithelial cell - binds to AR and induce growth factor -- Stromal cell - majority converts to dihydrotestosterone (DHT) via 5α-reductase type II binds to AR or diffuses to nearby epithelial cell -- Protein synthesis and development of BPH o Estrogen stimulate stromal tissue and androgen receptor

Contraceptives Government & Law Minors

o 30 of 50 states allow minors to provide their own consent for contraceptive services o Texas requires parental consent for prescription contraception o No states require parental consent for purchase of non-prescription, over the counter birth control o Texas is one of two states that does not allow state funds to be used to provide contraceptives to minors without parental consent (exception: Medicaid)

Contraceptives Government & Law Texas current events In 2012, the federal government decided to no longer fund Texas Medicaid's Women's Health Program (WHP) starting in 2013 if Planned Parenthood health centers were excluded from the program PP now operates without federal funding that previously covered 90% of expenses ($9:$1 federal match)

o 30,000 fewer women received care through WHP in 2013 than 2011 o 50% drop in total claims for birth control methods o 35% decline in women using most effective birth control methods o 27% spike in Medicaid births among women who previously used injectable contraception

Therapeutics of Sexual Dysfunction Erectile Dysfunction Testosterone Replacement Intraurethral Alprostadil Efficacy

o 43-65% overall effectiveness o Decreased effectiveness and inconvenient administration resulted in product being third-line option for patients with ED

Clomiphene (Clomid®) PCOS Treatment Dosing

o 50 mg PO qd x 5 days (start day 5 of menstrual cycle) o Max: 100 mg PO daily x 5 days x 6 cycles o No ovulation or pregnancy: discontinue at 3 cycles

Oral Planned Contraceptives Extended Cycle

o 84-day (12-week) cycle, with or without 7-day placebo -- Ethinyl estradiol (10-30 mcg) + progestin (<1 mg) o Effective contraceptive o Increased rate of breakthrough bleeding initially o Decreased amount of menstruation bleeding overtime, may lead to amenorrhea

Infertility

o < 35 years of age: 12 months o ≥ 35 years of age: 6 months o 85% of couples conceive in a 12 month period -- Most common factor affecting infertility: advancing maternal age o Fecundity rates start to decrease after age 30 -- ↑ rates of abnormalities and spontaneous abortion o Male fertility ↓ after age 35

LARC Subdermal progestin implants Effectiveness !!!!Return to fertility: within 30 days

o >99% o Overweight/obese (>130% IBW) potential for decreased efficacy

Other hormonal contraceptives Injectable progestins Effectiveness

o >99% effective with perfect use o 97% with typical use o Starts working immediately after injection o Special populations -- Reduces pain crises in women with sickle cell disease -- Reduces seizures in women with seizure disorders -- May be slightly less effective in obese patients

Premenstrual dysphoric disorder (PMDD) Pathophysiology

o ? due to low levels of the centrally active progesterone metabolite allopregnanolone and/or lower cortical γ-aminobutyric acid levels o ? due to low serotonin levels o Distinct pathophysiology from depression

Therapeutics of Sexual Dysfunction Erectile Dysfunction Testosterone Replacement Alprostadil

o AE: penile pain, urethral burning o Contraindications/precautions -- Pregnant partner (because of the possibility of drug transfer and induction of labor) -- Sickle cell disease -- Warfarin or other oral anticoagulants (rivaroxaban, apixaban, dabigatran) o Monitoring -- First dose should be given under supervision to monitor syncope, and all doses should be given with an empty bladder, maximum of two doses every 24 hours

Oral contraceptives Progestin only pills

o AKA POPs, minipills o Less effective than CHCs o Must be taken continuously (e.g. no placebo tablets) o Must take at same time every day -- 3 hour delay backup method x48 hours o May not block ovulation -- Higher risk of ectopic pregnancy

Therapeutics of Sexual Dysfunction Erectile Dysfunction Epidemiology

o Affects 50% of men older than 40 years o Age-related increase in incidence from 12.4% in men aged 40 to 49 years, up to 46.4% in men aged 60 to 69 years o Medications cause up to 10-20% of ED cases o Exerts substantial effects on quality of life

Infertility Risk Factors

o Age o Tobacco use o Alcohol o Illicit drug use o Overweight or underweight o Emotional factors o Occupational and environmental risk

PDE5i Pharmacokinetics

o All are metabolized by CYP3A4. o Strong and moderate CYP3A4 inhibitors, such as indinavir & ritonavir (HIV), ketoconazole (anti-fungal), erythromycin, increase plasma concentrations by 2 to 16x. o Grapefruit juice inhibits CYP in GI tract and can increase bioavailability of PDE5i. o CYP3A4 activators, such as rifampin (TB), reduce plasma level of PDE5i.

Therapeutics of Sexual Dysfunction Erectile Dysfunction PDE-5 Inhibitors Clinical Pearls

o All four are effective, and choice of drug is usually based on patient preference, cost, ease of use, and adverse effects o An adequate trial of PDE-5 inhibitor requires the use of at least 5 to 8 doses over a period of time (not in one day); if a patient does not respond to one agent after an inadequate trial, it is reasonable to try one of the other three agents rather than move to a second-line agent o Success increases with each use of the drug, even up to 6-8 attempts o A higher dose may be necessary if the first dose is ineffective

Candidates for hormonal contraception

o American Congress of Obstetrics and Gynecology (ACOG): after simple medical history and blood pressure measurement o Traditionally provided after breast & pelvic exams -- ACOG: annual pelvic exams recommended -- American College of Physicians: recommends against performing screening pelvic examination in asymptomatic, nonpregnant, adult women. Should still screen for cervical cancer when indicated via visual inspection and cervical swabs; not full pelvic examination

PCOS Treatment Pharmacological

o Androgen excess -- Hormonal contraceptives -- Intrauterine Device (IUD) o Insulin resistance -- Metformin -- Thiazolidinediones (TZDs) o Ovulatory simulating medications -- Clomiphene or aromatase inhibitors -- Gonadotropins (second-line)

Contraceptive methods differ in: o Effectiveness: difficult to measure o Safety o Patient preference

o Annual cost (2011 data) -- Many women default to less expensive methods (condoms, etc) due to cost and accessibility -- IUDs are most cost-effective over time but high up-front costs 5.5% use rate -- Studies show when cost barrier is removed, women are more likely to choose more effective methods -- Kaiser Permanente eliminated copays for IUDs, injectables, & implants 137% increase in use and ~1791 pregnancies averted

Other hormonal contraceptives Transdermal contraceptives Missed patch exchange

o Application delayed <48 hours and old patch still on no backup needed; apply new patch ASAP o Application delayed ≥48 hours new patch application ASAP & backup x7 days o If occurs in 3rd patch week, omit hormone-free week and apply new patch immediatel

Other hormonal contraceptives Transdermal contraceptives Instructions

o Apply to abdomen, buttocks, upper torso, or upper arm o Apply at beginning of menstrual cycle o Replace every week, allowing patch-free interval week 4

Oral Planned Contraceptives Quadraphasic (Natazia®)

o Approved 2010 for Oral contraceptive Heavy menstrual bleeding

Beyond ED: Taladafil (Adcirca®)

o Approved for Pulmonary Arterial Hypertension (PAH) to improve exercise ability o 40 mg, p.o., q.d.

Infertility Self-Care

o Best time for conception -- Intercourse 1-2 days prior to ovulation o Basal body temperature (BBT) o LH surge measurement kits -- First Response® Ovulation test -- Clearblue® Ovulation test -- Clearblue® Fertility Monitor -- OV-Watch Fertility Predictor

Other hormonal contraceptives Injectable progestins Typical candidates

o Breastfeeding o Intolerant to estrogens -- Headache -- Breast tenderness -- Nausea o Concomitant medical conditions where estrogen is not recommended o Adherence concerns

LARC Intrauterine devices (IUDs) Oral contraceptives + IUDs

o Can be taken in conjunction to treat other conditions -- Migraines -- Acne

Oral contraceptives Vomiting/severe diarrhea

o Can reduce efficacy of OCs o Follow same instructions as if missing CHCs: -- V/D <48 hours no redosing required -- V/D >48 hours use backup for 7 days after V/D subsides -- V/D during last week skip placebos and begin a new pack and use backup until 7 days of tablets are taken without GI symptoms -- Counsel if emergency contraception is warranted

Hypogonadotropic Hypogonadism Impaired secretion of gonadotropins (FSH/LH)

o Causes -- Congenital syndromes (less common) -- Tumors, head trauma, drugs, infections (more common) o Signs and Symptoms -- Decreased libido -- Decrease of energy and interest in physical activities -- Loss of muscle mass -- Mood changes

Infertility Self-Care

o Clearblue ® Fertility Monitor -- Detects LH and Estrogen -- Identifies up to 6 fertile days -- Accounts for menstrual cycle variability -- Expensive o OV- Watch Fertility Predictor -- Detects baseline chloride ion level peaks --> 4 days prior to LH surge and 5 days prior to estrogen o Pregnancy test 1 week after missed period -- Measures human chorionic gonadotropin (hCG) hormone

Therapeutics of Sexual Dysfunction Erectile Dysfunction PDE-5 Inhibitors Drug Monitoring

o Clinical symptoms o Visual complaints, loss of vision o Hearing loss o Blood pressure o Pulse o Palpitations or dizziness

Hypogonadotropic Hypogonadism Treatment

o Clomiphene √ Gonadotropins (hCG, LH, and FSH) o For desired fertility o hCG -- Binds to Leydig cells LH receptors and stimulates testosterone production and Induces spermatogenesis -- Titrate based on testosterone levels (target: middle normal values) o Can use hCG and FSH-containing preparations together

Male birth control Male birth control hormone injections

o Combination progestogen and testosterone o Given every 8 weeks o Mechanism: suppression of spermatogenesis o 98.5% effective o Reversible within 52 weeks for 95% of men o ADRs: -- Acne -- Injection site pain -- Increased libido -- Mood disorders -- 2.8% depressed mood/depression -- 0.6% severe depression o Trial stopped early due to mood disorders

Emergency (Postcoital) Contraceptives Anti-progestin Mifepristone (RU38486, RU-486, Mifeprex®) Therapeutic Use o Termination of early pregnancy

o Competitive antagonist of PR-A & PR-B o Induces decidual necrosis leads to blastocyst detachment which, in turn ends pregnancy o Blocks development of secretory endometrium results in induces menstruation o Suppresses gonadotropin release (mechanism unknown) results in delays or prevents ovulation

Polycystic Ovary Syndrome (PCOS)

o Condition in which a woman's level of the sex hormones, estrogen, and progesterone are out of balance -- Leads to the growth of ovarian cysts -- Most common cause of anovulatory bleeding o Signs and symptoms (typical triad): -- Anovulation or oligoanovulation --> Amenorrhea or oligomenorrhea -- Acne and hirsutism -- Metabolic syndrome

Oral contraceptives Adverse events Management

o Confirm ADR is due to drug o Select a product with more/less of target hormone --High vs. low vs. ultra-low dose estrogen -- Increasing/decreasing progestin doses -- Switch progestin to target ADRs o Generally, wait until next pack

Oral contraceptives Combined hormonal contraceptives

o Contain an estrogen (ethinyl estradiol or estradiol) and a progestin (many types) o Traditional form of birth control o AKA CHCs, COCs

Oral Planned Contraceptives Monophasic

o Contains the same amount of E & P for about 21 days, then about 7 days of placebo o First oral contraceptive (approved 1960) -- Enovid® = mestranol (150 mcg) + norethynodrel (10 mg) o Currently -- Ethinyl estradiol (20-50 mcg) + progestin (<1 mg)

Female Sexual Dysfunction Flibanserin o Indication: acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women o Administration -- Bedtime to reduce risk of hypotension, syncope, injury, and CNS depression (somnolence, sedation)

o Contraindications -- Alcohol -- Strong or moderate CYP3A4 inhibitors -- Start flibanserin 2 weeks after completion of CYP3A4 inhibitor -- Start CYP3A4 inhibitor 2 days after last dose of flibanserin -- Hepatic impairment o Discontinue after 8 weeks if no improvement in symptoms

Non-Oral Planned Contraceptives Intrauterine Device

o Copper T (ParaGard®) -- Releases copper -- Causes immune response hostile to sperm -- Intended for 10 years of use, shown to be effective for up to 20 years

Anatomy of Penis Mechanics of an erection

o Corpora cavernosa -- Cylindrical structures with interconnected chambers filled with blood. o Urethra within corpus spongiosum -- Spongiosum keeps urethra open to allow exit of semen o Inner layer of tunica albuginea -- Tough strong membrane

Unintended pregnancy Consequences for health care system:

o Cost of one Medicaid-covered birth in US was ~$13,000 in 2008 (vs. one year of contraceptive care = $257) o In 2008, $1,900,000,000 spent on publicly funded family planning resulting in $7,000,000,000 Medicaid savings o Every $1 spent on public funding for family planning saves taxpayers $3.74 in pregnancy-related costs o In 2006, publicly funded family planning services prevented ~1,940,000 pregnancies and ~810,000 abortions

Oral Planned Contraceptives Estrophasic (Estrostep®Fe)

o Day 22-28 tablets contain ferrous fumarate o Aims -- Low hormone content (minimize estrogen-related side effects) -- Maintains good cycle control o Also approved to treat acne vulgaris

Hormonal contraception Oral contraceptives: other benefits

o Decreased menstrual cramps o Decreased ovulation pain (mittelschmerz) o Decreased menstrual blood loss o Menstrual regularity o Decreased iron-deficiency anemia o Reduced ovarian cancer rates o Reduced endometrial cancer rates o ? Reduced ovarian cysts, ectopic pregnancy, pelvic inflammatory disease, endometriosis, uterine fibroids, benign breast disease

Endometriosis Incidence -- 6-10% of reproductive age women -- Up to 50% of women with infertility

o Definition -- Chronic inflammatory disorder -- Endometrial-like tissue located outside the uterus -- Characterized by pelvic pain and infertility

Menstrual disorders Dysmenorrhea

o Definition: crampy pelvic pain just prior to or concurrent with menses -- Primary: normal pelvic anatomy & physiology (90%) -- Secondary: underlying pelvic pathology (10%) o Epidemiology -- Incidence: 16-90% -- Decreased productivity/absence from school or work

Intrauterine, Intracervical, Intravaginal Insemination

o Delivery of prepared semen sample to intended site during ovulation -- NOT IN VITRO FERTILIZATION o Sperm washing -- Removal of dead and slow moving sperm -- WBC and prostaglandins

Non-Oral Planned Contraceptives Injectable Progestin only

o Depo-Provera® -- Medroxyprogesterone acetate (150 mg in 1 mL) -- Deep intramuscular injection once every 3 months o Depo-subQ Provera® -- Medroxyprogesterone acetate (104 mg in 0.65 mL) -- Subcutaneous injection once every 3 months o Associated with decreased bone mineral density

Endometriosis

o Diagnosis -- Visualization at surgery -- Imaging has variable ability to detect depending on location of endometriomas o Signs/symptoms -- Pain ≥ 6 months -- Dysmenorrhea -- Cyclic nausea, early satiety, bladder distension o Goals of therapy -- Reduction of pain -- Fertility

Therapeutics of Sexual Dysfunction Erectile Dysfunction PDE-5 Inhibitor Adverse Effects

o Dose-related, vasodilation o Sudden hearing loss o Vision changes

Oral Planned Contraceptives Progestin-only (minipills)

o Drugs -- Norethindrone (0.35 mg) (Micronor®, Nor-QD®) -- Norgestrel (0.075 mg) (Ovrette®) o Main Effect: Increases thick cervical mucus secretion, which prevents sperm penetration o Slightly less efficacious than combination o Irregular and unpredictable breakthrough bleeding

Contraceptives Pharmacology Planned Contraceptives Primary goal = Suppress ovulation

o Drugs = Progestin with/without Estrogen o Mechanism of action = both P & E suppress the release of -- GnRH -- LH (ovulation) -- FSH (follicle maturation)

Other hormonal contraceptives Vaginal ring o Nuvaring®

o EE ~15 mcg/day + etonogestrel ~120 mcg/day o 54mm flexible ring, 4mm thick o As effective as CHC OCs -- Including overweight/obese patients o Does not protect against STIs

Hormonal contraception Oral contraceptives: adverse events cont

o Early symptoms improve spontaneously by 3rd cycle -- Nausea, bloating -- Breakthrough bleeding --- Expected within first 6 months --- After 6 months or severe bleeding should consider change -- Do not make changes until 2-3 months o Weight gain -- Component of estrogen and progestin

IVF Risks

o Ectopic pregnancy o Multiple births o Premature delivery o Birth defects o Ovarian hyperstimulation syndrome o Miscarriage

Abortifacients

o End pregnancy by emptying the uterus o Effective for ~10 weeks after first day of last period o First tablet, mifepristone, is taken at clinic -- Blocks endogenous progesterone which is required to maintain pregnancy -- Patient also takes antibiotics to prevent infection

Benign Prostatic Hyperplasia Normal Prostate Physiology

o Epithelial -- Produces prostatic secretions -- Androgens stimulate growth o Stromal tissue -- α1-adrenergic receptors stimulated by norepinephrine causes smooth muscle contraction -- Compress urethra, reduce urethral lumen, and decrease urinary bladder emptying o Capsule -- Outer shell of prostate -- Fibrous connective tissue and smooth muscle -- α1-adrenergic receptors stimulation via NE contracts around urethra

PCOS Treatment Menstrual Abnormalities

o Estrogen -- Increases sex hormone-binding globulin reducing bioavailable androgen -- Endometrial stabilization o Progestins -- Suppresses LH levels and ovarian androgen production -- Medroxyprogesterone (MPA) depot o Combined hormonal contraception (CHC) -- First-line therapy for acne and hirsutism -- Regulate menstrual bleeding -- Suppression of ovarian hormones and androgen production -- < 35 mcg ethinyl estradiol + desogestrel, norgestimate, or drospirenone +ethinyl estradiol o IUD

Non-Oral Planned Contraceptives Vaginal Ring NuvaRing®

o Flexible, transparent ring (diameter = 54 mm) placed in vagina o Remains in place continuously for 3 weeks, followed by a ring-free week o Each ring contains -- Ethinyl estradiol (2.7 mg), releasing 15 mcg/day -- Etonorgestrel (11.7 mg), releasing 120 mcg/day o Equal effectiveness as combination oral contraceptives o Inadvertent expulsion is a concern, but uncommon.

Endometriosis Risk factors

o Genetics o Obstruction of menstrual outflow (e.g. mullerian anomalies) o Prolonged exposure to endogenous estrogen -- Early menarche -- Late menopause -- Obesity o Red meat and trans fats o Fruits and green vegetables decreased risk

Leuprolide Premenstrual dysphoric disorder (PMDD) Pharmacologic treatment

o GnRH agonist o Expensive o IM injection o Works within 1-2 months o ADRs: due to hypoestrogenism (vaginal dryness, hot flashes, bone demineralization)

LARC Intrauterine devices (IUDs) Nulliparous women

o Historical contraindication/caution o No longer a contraindication; benefit > risk o Mirena package insert recommends in women with at least one child o Skyla & ParaGard package insert recommended for all women

Etiology

o Hypogonadotropic Hypogonadism -- Low FSH and LH low testosterone o Hyperprolactinemia (refer to Pituitary Disorder slides) -- Prolactin inhibits hypothalamic GnRH secretion o Obesity -- SHBG levels decrease decrease in total testosterone -- Increase in estradiol decrease free testosterone o Genetics

Menstrual disorders Amenorrhea Pahtophysiology

o Hypothalamus-pituitary-adrenal (HPA) axis or -- Anorexia, bulimia, intense exercise, and/or stress hypothalamus does not secrete adequate GnRH -- Thyroid disease, hyperprolactinemia, dopaminergic drugs altered secretion of FSH and LH by pituitary o Hypothalamus-pituitary-ovarian axis -- Premature ovarian failure: insufficient estrogen production no viable follicles; may be genetic -- Anovulation: no ovulation follicle cannot convert to corpus luteum hormone abnormalities o Uterus/outflow obstruction -- Imperforate hymen -- Uterine agenesis -- Asherman's syndrome -- Cervical stenosis o Rule out pregnancy

Long-acting reversible contraception (LARC)

o IUDs & Implants o Highly efficacious (≥99%) o Quickly reversible o Minimal adherence concerns o Underutilized in US vs. other countries -- Up to 7% in all women -- Up to 11% in women age 25-34 o Essentially all women are candidates o Whether or not women have given birth already should not be considered

Abortifacients Premedicating

o Ibuprofen ~30 minutes prior to misoprostol o Anti-nausea meds if needed o Do not take aspirin o Heating pad on abdomen

Therapeutics of Sexual Dysfunction Erectile Dysfunction General Approach

o Identify and, if possible, reverse the underlying cause o Follow heart-healthy lifestyle (e.g., physical fitness, weight loss, low cholesterol diet, no excessive alcohol intake, no smoking) o Ideal ED treatment -- Fast onset -- Convenient to administer -- Cost-effective -- Low incidence of serious adverse effects (AE) -- Free of drug interactions

Oral contraceptives Routine daily administration of COCs p2

o If tablets were missed the last week of active pills -- Omit the hormone-free interval by finishing active drug tablets and then starting a new pack -- Use backup for 7 days o For all situations when ≥2 tablets are missed, consider counseling on emergency contraception o Consider other formulations for women who routinely struggle with adherence

Oral contraceptives Routine daily administration of COCs

o Importance of routine daily administration -- Ensure consistent plasma concentrations -- Improve adherence o Missed doses for COCs -- Specific instructions for each formulation available in package insert -- CDC strives to simplify instructions

Benign Prostatic Hyperplasia Combination Therapy α-adrenergic antagonist and 5α-reductase inhibitor

o Indication -- Symptomatic patients with increased prostate size -- Elevated PSA (> 1.5 ng/mL), -- Those with risk of disease progression, or -- Patients unresponsive to monotherapy o Multiple Treatment of Prostate Symptoms Study (MTOPS) o Combination of Avodart and Tamsulosin (COMBAT)

LARC Intrauterine devices (IUDs) Mechanisms:

o Inhibition of sperm migration o Damaging or disrupting ovum transport o ? Damaging fertilized ovum o Progestin-containing: -- Endometrial suppression -- Thickening cervical mucus

Emergency contraception Mechanism Prevents unwanted pregnancy after unprotected or inadequately protected intercourse

o Inhibits or delays ovulation o No evidence of effect on implantation or disruption of a fertilized, implanted egg o Will not disrupt an implanted embryo; not an abortifacient

Non-Oral Planned Contraceptives

o Injectable (subcutaneous or intramuscular) -- Combination (outside US) -- Progestin-only o Subdermal implant o Transdermal o Vaginal ring o Intrauterine device

Other hormonal contraceptives Injectable progestins Instructions

o Injected every 3 months at doctor's office by deep IM injection in gluteal or deltoid muscle or subcutaneously into the thigh o Inject within 5 days of bleeding onset

Other hormonal contraceptives Injectable progestins Mechanism !!!Does not protect against STIs!!!

o Injected hormones release over time o Sustained progestin exposure blocks LH surge inhibits ovulation o In rare event of ovulation -- Reduce ovum motility in fallopian tubes -- Thin endometrium reduced change for implantation o Thicken cervical mucus barrier for sperm

LARC Subdermal progestin implants Insertion

o Insert between days 1-5 of cycle no backup o Insert other days backup x7 days o Currently taking CHC OCs: insert within 7 days after last active OC tablet o Currently using progestin-only contraceptive methods: don't skip days between POPs, IUDs, or DMPA and implant

Other hormonal contraceptives Vaginal Ring Insertion

o Insert ring and leave in place 3 weeks -- Sit or lay in comfortable position -- Compress ring between thumb and index finger push into vaginal canal -- Precise location not as crucial as diaphragms & cervical caps because hormones are absorbed anywhere in vagina -- Cannot be inserted "too far"

LARC Intrauterine devices (IUDs) Use

o Insertion & Removal: -- Insertion @ 1:10; removal @ 0:49 -- Usually inserted during period o Effectiveness -- > 99% -- Not influenced by "typical use" o Not effective at preventing STIs

Physiology of Penile Erection

o Interconnected chambers inside the corpora cavernosa where blood is trapped for erection. o Trabecula- partitions of smooth muscle and connective tissue o Inflow and outflow equal when penis is flaccid ∆ no net change in pressure, size, or blood flow o Relaxes smooth muscles o Dilated cavernosal artery increases inflow o Out flow veins are decreased during erection

LARC Subdermal progestin implants ADRs:

o Irregular menstrual bleeding 11% discontinuation rate -- 22% become amenorrheic -- 18% prolonged bleeding -- 34% prolonged spotting -- Consider a short course of estrogens for 10-20 days to help o Drug interactions with CYP inducers (rifampin, phenytoin, carbamazepine) are of debatable concern

Contraindications of PDE5i Nitrate Medications

o Isosorbide mononitrate: prophylaxis for angina pectoris o Nitroglycerine: prophylaxis & management of angina pectoris o Risk for significant and catastrophic hypotension

Hormonal contraception Oral contraceptives: adverse events

o Lack of protection against STIs o Small increases in blood pressure o ? Increased breast cancer o Thromboembolism -- Estrogens produce increased factor VII, factor X, and fibrinogen -- Higher risk in women with other risk factors -- Thromboembolism mortality is 3x higher in OC users -- Newer progestins even higher risk (e.g. drospirenone, desogestrel, norgestimate

Emergency contraception Oral progestin-based emergency contraception

o Levonorgestrel 1.5mg tablet x1 dose -- Plan B One Step or Next Choice One Dose -- Take within 72 hours of unprotected intercourse-->Sooner is better -- May have some effect for 5 days *** Ulipristal or copper IUD may be a better option -- Preferred for adherence and ADR concerns -- Available OTC with no age restrictions o Levonorgestrel 0.75mg tablet q12h x2 doses -- Available OTC to patients ≥ 17 years

PDE6 & Phototransduction

o Light activates rhodopsin o Rhodopsin activates a G protein - transducin o Transducin activates PDE6 o PDE6 degrades cGMP o cGMP-gated Na+ channel closes o Photoreceptor cell hyper polarizes o Stops glutamate release o Light perception

PDE5

o Localized in blood vessel & penile smooth muscle cells o Concentration in corpus cavernosum > systemic vasculature o Not in --- Cardiac myocytes --- Cardiac conduction tissues

Therapeutics of Sexual Dysfunction Erectile Dysfunction PDE-5 Inhibitors Key Counseling Points

o Make a follow-up appointment with prescribe if the drug is not effective o Side effects are usually mild and transient-headache, flushing, GI upset o If prolonged erection (>4 hrs) occurs, contact the physician immediately o Inquire if the patient is taking any drugs for their heart, blood pressure, or prostate; if yes, follow up with specific questions about nitrates, alpha-blockers, and QT-interval prolonging drugs

Stage One: Controlled Ovarian Stimulation

o Manipulate follicular development for oocyte retrieval o Oral contraceptives -- Up to 28 days preceding menstrual cycle -- Pertinent for irregular or long menstrual cycles -- Suppresses any ovarian cysts

Other hormonal contraceptives Injectable progestins Missed injections

o May work up to 14 weeks o Pregnancy test when ≥13 weeks between injections for IM formulation or ≥14 weeks with subcutaneous formulation

Emergency contraception Ulipristal

o Mechanism -- Selective progesterone receptor modulator -- Delays ovulation o Dosing: 30mg PO x1 within 5 days of intercourse o Non-inferior to levonorgestrel-containing EC -- 2x less effective in obese women o RX only o Wait until next cycle to restart hormonal contraception o Use backup x7 days

Hyperprolactinemia

o Mechanism not well understood -- ↑ prolactin may inhibit GnRH -- ↓ secretion of LH and FSH o May act directly on GnRH neurons o Indirect effects

Therapeutics of Sexual Dysfunction Erectile Dysfunction Testosterone Replacement Alprostadil

o Mechanism of action -- Prostaglandin E1 -- Stimulates adenylyl cyclase increasing production of cAMP, a secondary messenger that decreases intracellular calcium concentration and causes smooth muscle relaxation of arterial blood vessels -- Enhances blood flow to and blood filling of the corpora o Indications -- FDA-approved as monotherapy for management of ED

PCOS Summary Ovulatory dysfunction Woman's level of the sex hormones, estrogen, and progesterone, are out of balance

o Menstrual abnormalities -- Combined hormonal contraception (CHC) o Ovulatory Stimulating Agents -- Clomiphene -- +/- Metformin -- Aromatase Inhibitors -- Gonadotropins o Surgical intervention -- Ovarian drilling o IVF

Abortifacients Second tablet, misoprostol (Cytotec®), is taken at home, 24-48 hours later

o Might be filled at pharmacy; often given in clinic o Works by inducing uterine contractions o What to expect: -- Cramping and bleeding 1-4 hours after dose -- Large blood clots or tissue -- Similar to "really heavy, crampy period" -- May last several hours (average ~4-5) -- May experience nausea/vomiting -- May experience cramping for 1-2 days after

Stage One: Controlled Ovarian Stimulation Gonadotropins

o Mimic natural follicular recruitment & maturation o Hypogonadic hypogonadism: FSH + LH (Menotropins) o Normal pituitary: FSH alone or Menotropins o Dose: 150-225 IU daily x 7-12 days o $350 per day o Proper storage, preparation, and injection education needed

Premenstrual dysphoric disorder (PMDD) Nonpharmacologic treatment

o Minimal evidence o Try for first two months while maintaining a symptom journal o Reduce caffeine, sugar, and sodium intake o Increase exercise

Non-Oral Planned Contraceptives Intrauterine Device Levonorgestrel (Mirena® & Skyla®)

o Mirena® -- Releases 20 mcg/day initially, 10 mcg/day after 5 years -- Approved for 5 years of use, shown to be effective up to 7 years o Skyla® -- Releases 14 mcg/d initially, 6 mcg/day after 3 years -- Approved for 3 years of use

Therapeutics of Sexual Dysfunction Erectile Dysfunction Testosterone Replacement Intracavernosal Alprostadil Efficacy

o More effective by intracavernosal than intraurethral route due to improved bioavailability injected directly into corpora cavernosum o 70-90% overall efficacy o Although efficacious, 30-50% of patients voluntarily discontinue therapy -- Lack of perceived effectiveness -- Inconvenience of administration -- Unnatural, spontaneous erection -- Needle phobia -- Loss of interest -- Cost of therapy

Oral contraceptives Placebo pills

o Most formulations -- "Minipills" must be taken continually o "Pill-free interval" o 4-7 days -- Less placebo days reduced hormone fluctuation o May contain supplements o Counseling: encourage patients to take placebos to enhance adherence

Unintended pregnancy Consequences for parents:

o Mother more like to experience physical abuse o Partner relationships more likely to dissolve

Aromatase Inhibitors PCOS Treatment Letrozole (Femara®) and Anastrozole (Arimidex®) Dosing 2.5-7.5 mg daily on day 3-7

o Multicenter, double-blind, randomized clinical trial (n = 750 subjects) showed marked superiority in live birth rate or Letrozole over Clomiphene in PCOS o Not FDA approved for ovulation induction o Mechanism of action -- Aromatase, a cytochrome P450 enzyme that catalyzes conversion of androgens to estrogens -- Nonsteroidal competitive inhibitor of aromatase enzyme system reduction in estrogen

Pathophysiology Endometriosis

o Multifactorial o Likely due to retrograde menstruation endometrial tissue displacement

Contraceptives Pharmacology Progestins - Pharmacokinetics Metabolism

o Natural progesterone has very short T½ (5 min) o Synthetic progestins have much longer T½ -- Norethindrone T½ = 7 h -- Gestodene T½ = 12 h -- Norgestrel T½ = 16 h -- Medroxyprogesterone acetate (MPA) T½ = 24h

Emergency contraception ADRs for all hormonal EC:

o Nausea o Vomiting -- Within 3 hours of dose retake -- Can pre-medicate with RX or OTC medications o Bloating o Menstrual cramps o Headaches

Pathophysiology of contraception Incidence & epidemiology ~6 million pregnancies/year in US

o Nearly half are unintended --- Half end in abortion ~11% occur in women using no contraception; ~89% are attributable to inconsistent or imperfect use or contraceptive failure

LARC Subdermal progestin implants

o Nexplanon (formerly Implanon) o 4cm long implant -- 68mg of etonogestrel -- Releases 60 mcg/day o Placed under skin of upper arm using preloaded inserter o Mechanism: -- Suppression of ovulation -- In event of ovulation, tickens cervical mucus and produces atrophic endometrium

Therapeutics of Sexual Dysfunction Erectile Dysfunction PDE-5 Inhibitors Drug Interactions

o Nitrates o Anti-hypertensive medications o CYP3A4 inhibitors (e.g., cimetidine, ketoconazole, itraconazole)

LARC Intrauterine devices (IUDs) Return to fertility

o No long-term impact on fertility o Return to fertility time similar to OCs (~30 days)

Therapeutics of Sexual Dysfunction Erectile Dysfunction TESTOSTERONE REPLACEMENT Mechanism of Action & Indications

o Normal testosterone is necessary for appropriate sex drive and testosterone may be responsible for optimal nitric oxide production o Testosterone replacement regimens supply exogenous testosterone and restore serum testosterone levels to normal range (300 to 1,100 ng/dL) o Indications -- Primary or secondary hypogonadism (confirmed by presence of decreased libido and low serum concentrations of testosterone)

PCOS Treatment Non-pharmacological

o Obesity: weight loss (diet and exercise) o Surgery

Physiology of Penile Erection Nocturnal erection

o Occurs mostly during rapid-eye-movement (REM) sleep o Proposed mechanism: the cholinergic neurons in the lateral pontine tegmentum are activated while the adrenergic neurons in the locus ceruleus and the serontonergic neurons in the midbrain raphe are silent during REM sleep

Menstrual disorders Heavy menstrual bleeding

o Old term: menorrhagia o Definition: blood loss >80 mL/cycle or bleeding >7 days/cycle o Epidemiology -- 20-30% of women -- 12-15% of GYN referrals -- With coagulation disorders: 98-100% incidence

Non-Oral Planned Contraceptives Transdermal Patch Ortho Evra®

o One patch once a week for 3 weeks, followed by no patch for 1 week o Each 20 cm2 patch contains -- Ethinyl estradiol (0.75 mg), releasing 20 mcg/day -- Norelgestromin (6 mg), releasing 150 mcg/day o Equal effectiveness as combination oral contraceptives

Testosterone Formulations

o Oral - not recommended due to first pass effect & hepatotoxicity o Buccal (Striant®)(b.i.d.) o IM injection (Depo-testosterone®, Delatestryl®)(once 2-4 weeks) o Transdermal patch (Androderm®)(q.d.) o Gel (Androgel®, Testim®)(q.d.) o Transdermal spray (Fortesta®)(q.d.) o Transdermal solution (Axiron®)(q.d.) o SubQ inplant pellet (Testopel®)(once 3-6 months)

Other hormonal contraceptives Transdermal contraceptives

o Ortho-Evra ® o EE 0.75mg + norelgestromin 6mg (CHC) o Possibly less effective in overweight/obese women -- In studies, was as effective as CHC OCs in women <90 kg o Better adherence than OCs o 1/3 of pregnancies in trials were in women >90kg; not recommended first-line

PCOS Treatment Ovarian Drilling

o Ovarian Drilling -- Laparoscopic surgery - laser used to remove thick outer layer of ovaries -- Reduce testosterone levels and increase ovulation -- 50% success after 1st year of surgery -- LH/FSH ratio <2, testosterone levels >4.5 nmol/L, and free androgen index >15= poorer response o Risk -- Bleeding -- Infection -- Organ damage (bowel, bladder, ovaries) -- Early onset of menopause

Clomiphene PCOS Treatment Adverse Effects

o Ovarian enlargement o Ovarian hyperstimulation syndrome o Visual disturbances o ↑ risk of ovarian cancer o PCOS: use lower dose o Multiple births o Other: mood swings, headache, hot flashes, breast discomfort, abnormal uterine bleeding, bloating, nausea, vomiting

Clomiphene (Clomid®) PCOS Treatment Pharmacokinetics

o Ovulation 5-10 days after course of treatment o Most efficacious in non-obese women (BMI <30 kg/m2)

Female Sexual Dysfunction Hypoactive Sexual Desire Disorder

o Persistent or recurrent deficiency or absence of sexual desire or receptivity to sexual activity o Prevalence between 5.4-13.6% o Age -- 40-60 years: menopause, depression, chronic disease -- Younger women: situational circumstances (dysfunctional relationships), chronic diseases, depressions, gynecologic disorders, medications (i.e., SSRIs)

Pharmacist's role in contraception

o Pharmacist can dispense birth control under protocol to patients o California: -- Senate Bill 493 (2013): Pharmacists can furnish hormonal contraception based on a statewide protocol:

Prostaglandin E1 (Alprostadil) Alprostadil Urethral Suppository (Muse®) MUSE should not be used for sexual intercourse with a pregnant woman unless the couple uses a condom barrier.

o Pharmacological Effect -- Same as PGE1 injection o Therapeutic Use -- Erectile dysfunction o Adverse effects -- Penile pain -- Urethral burnin

Benign Prostatic Hyperplasia α-Adrenergic Antagonists Third-generation

o Pharmacologically selective for prostatic α1A-adrenergic receptors o Side effects: tiredness, asthenia, anejaculation, flu-like symptoms, nasal congestion, floppy iris syndrome (tamsulosin) -- Inform ophthalmologist about medications -- If not started on medication, avoid until after eye surgery complete o Dose: initiation at lowest effective maintenance dose (titration not necessary)

Therapeutics of Sexual Dysfunction Erectile Dysfunction Pharmacologic Treatment Options

o Phosphodiesterase inhibitors (first-line) o Intracavernosal and intraurethral alprostadil (second- and third-line) o Testosterone replacement (IX: hypogonadism)

Contraceptives Pharmacology Progestins - Pharmacodynamics Preparation & maintenance of Pregnancy

o Pituitary - Inhibition of GnRH, FSH, & LH release, thus suppression of ovulation !!!! Low dose of progestins does not always suppress ovulation! o Cervix - Thick mucus and cellular secretion, which prevents sperm penetration !!!! *** Important for efficacy of low-dose progestin-only pills! o Uterus -- Promotes secretory changes in the uterus to prepare for implantation of the fertilized egg -- Decreases uterine & tubal motility -- Initiate menstruation upon withdrawal o Breast - Proliferation of acini in mammary glands

Affordable Care Act Health plans written after August 2012 must cover contraceptive methods, services, and counseling without out-of-pocket expense

o Plans are allowed to limit coverage to some generic drugs and devices o Plans also must cover preventative services such as well-woman visits (pap smears, cancer screenings, etc) and prenatal care -- Some exceptions Burwell v. Hobby Lobby Inc, 2014: Corporations in which <5 people own >50% of stock may choose to exclude contraception coverage from their employees' health insurance plans under the ACA if use of contraceptives violates their religious beliefs.

Infertility Self-Care √ First Response ® and Clearblue®

o Predicts most fertile two days of cycle o Over 99% accurate in detecting the LH surge o First morning urine o Clearblue® is less expensive

Stage Three: Luteal Phase Support Progesterone

o Prepares endometrium for implantation o IM dosing -- Progesterone in oil: 50 mg daily -- 17-α-hydroxyprogesterone every 3 days o Vaginal dosing -- Progesterone vaginal gel 8% 90 mg daily or BID -- Vaginal insert 100 mg BID or TID o Administered until pregnancy test or 7-9 weeks gestation

Goals of therapy

o Prevention of pregnancy o Prevention of STIs (condoms) o Improvements in menstrual cycle regularity (hormonal contraceptives) o Improvements in other chronic health conditions (migraines, acne, etc with hormonal contraceptives) - 58% of indications o Perimenopause management

Emergency (Postcoital) Contraceptives Progestins Levonorgestrel Actions

o Prevents/delays ovulation (suppression of GnRH, FSH, LH) o Prevents fertilization (reduction of tubal transport of sperm and/or ovum) DOES NOT PREVENT IMPLANTATION!!!! Statement from International Federation of Gynecology and Obstetrics (FIGO): "Review of the evidence suggests that levonorgestrel emergency contraceptives cannot prevent implantation of a fertilized egg."

Menstrual disorders Dysmenorrhea Pathophysiology

o Primary: PG & LT release into menstrual fluid inflammatory response + vasopressin-mediated vasoconstriction o Secondary: endometriosis, pelvic inflammatory disease, uterine fibroids

Physiology of Penile Erection Psychogenic erection

o Produced by audiovisual stimuli or fantasy o Impulses from the brain modulate the spinal erection centers (T11-L2 & S2-S4) to activate the erectile process o Impaired in patients with spinal injury above T9; but partially preserved in injury at T12 or below

Physiology of Penile Erection Reflexogenic erection

o Produced by tactile stimuli to the genital organs. o Impulses reach the spinal erection centers; some travel to the brain, resulting in sensory perception, while others activate the autonomic nuclei to send messages via the cavernous nerves to the penis to induce erection. o This type of erection is preserved in patients with upper spinal cord injury.

Contraceptives Pharmacology Oral Planned Contraceptives Progestins used in Oral Contraceptives

o Progesterone is inactive orally, high first pass metabolism (Micronized, high-dose formulations can achieve sufficient plasma level) o Synthetics (C17-ethinyl) are orally active & metabolized slowly

Emergency (Postcoital) Contraceptives

o Progestins o Selective Progesterone Receptor Modulator (Ulipristal) o Anti-Progestin (Mifepristone)

PDE5i Effective in many types of severe ED patients

o Prostate cancer -- After radiation or nerve-sparing radical retropubic prostatectomy o Severe vascular disease o Diabetes o Depression

Clomiphene (Clomid®) PCOS Treatment Mechanism of action

o Racemic mixture consisting of zuclomiphene and enclomiphene o Acts on level of hypothalamus on estrogen receptors for longer durations than estrogen o Interferes with receptor recycling depleting hypothalamic ER inhibiting estrogen negative feedback o Impairment of negative feedback increases pulsatile GnRH secretion increased FSH and LH release for ovarian follicular growth

Menstrual disorders Heavy menstrual bleeding Goals of Therapy

o Reduce menstrual flow o Improve quality of life o Avoid surgery

Other hormonal contraceptives Transdermal contraceptives Patch detachment

o Released hormones for 9 days o Detachment <24 hours no backup needed; new patch application ASAP or reapply old patch o Detachment >24 hours new patch application ASAP & backup x7 days o If occurs in 3rd patch week, omit hormone-free week and apply new patch immediately

Other hormonal contraceptives Vaginal Ring Monthly Upkeep

o Remove ring after 3 weeks, maintain hormone-free interval for 7 days -- Removal similar to insertion -- Place into foil patch, then discard o Insert new ring on same day of week as previous cycle

Therapeutics of Sexual Dysfunction Erectile Dysfunction Testosterone Replacement Efficacy

o Restores muscle strength and sexual drive o Improves mood o Usually observed within days or weeks of testosterone replacement initiation o Do not directly correct erectile dysfunction but improves libido

Normal Prostate Physiology Primary Functions

o Secrete fluids that make up 20-40% of ejaculate volume o Provide secretions with antibacterial effect

Therapeutics of Sexual Dysfunction Erectile Dysfunction Testosterone Replacement Testosterone Concentrations

o Secretion pattern of testosterone follows a circadian pattern, with highest serum concentrations in the morning hours and lowest at night (~ 10pm) o Typically measured in early morning (~ 8am) o Low measured testosterone is confirmed with a repeat measurement on a separate day

Gonadotropins PCOS Treatment

o Seldom used in ovulation induction (mainly for assisted reproductive technology or hypogonadotropic hypogonadism) o Derived from urinary extracts or recombinant technology o Highly purified FSH (hFSH) vs Recombinant FSH (rFSH) -- No differences in clinical pregnancy -- hFSH=FSH and LH activity

Gonadotropins PCOS Treatment Adverse Effects

o Serious adverse effects -- Ovarian hyperstimulation syndrome (OHSS) -- Thromboembolic events -- Hypersensitivity reactions -- Abnormal ovarian enlargement -- Acute respiratory distress syndrome -- Ectopic pregnancy o Common adverse effects -- Headache -- Abdominal pain -- Injection site reaction

Therapeutics of Sexual Dysfunction Erectile Dysfunction CVD and ED

o Sexual function can be strenuous, patients should be assessed to make sure they are physically fit enough for sexual activity before being treated for ED o Sexual activity is reasonable for patients with CVD who are at low risk of CV complications o Cardiac rehabilitation and regular exercise can be useful to reduce the risk of cardiovascular complications with sexual activity for patients with CVD o Patients with unstable, decompensated, and/or severe symptomatic CVD should defer sexual activity until their condition is stabilized and optimally managed.

Therapeutics of Sexual Dysfunction Erectile Dysfunction PDE-5 Inhibitors Key Counseling Points

o Sexual stimulation is necessary o Onset of effect is 30-60 minutes for sildenafil, avanafil, and vardenafil, and up to 120 minutes for tadalafil o Faster onset occurs on an empty stomach; avoid high fat meals with vardenafil, sildenafil, and avanafil o Duration of action -- 4 hours for sildenafil and vardenafil -- Up to 36 hours for tadalafil o Tadalafil approved for daily-use dosing and PRN

Physical Examination and Labs

o Small testicular size or abnormal pattern of male hair growth o Varicoceles o FSH o Testosterone o Prolactin levels o Semen analysis

Intravaginal insemination (IVI)

o Sperm sample placed directly into the vagina o Can be done at home o Less expensive and less effective

Stage Two: Oocyte Retrieval Chorionic gonadotropin

o Stimulates effect of LH surge on oocyte maturation o Oocyte retrieval 34-36 hours after hCG o Dose -- Urinary: 5,000-10,000 IU IM x 1 -- Recombinant: 250 mcg SC x 1 o Once injected: discontinue GnRH analog and gonadotropin o Typically transfer 2 embryos -- Single embryo recommended in women < 35 years -- Poorer prognosis: transfer more embryos

Endometriosis √ Non-pharmacologic treatment

o Surgery often required; can be used first-line -- Excision -- Fulguration -- Laser ablation -- Drainage of endometriomas

LARC Intrauterine devices (IUDs)

o T-shaped plastic or metal frames that are inserted into the uterus by a healthcare professional o Prolonged contraceptive benefits

Anovulation Laboratory Tests

o TSH -- 0.5-4.7 microIU/mL o Prolactin -- Non-pregnant women: < 25 mcg/L -- Pregnant women: 34-386 mcg/L o Testosterone -- Female: < 62 ng/dL

Beyond ED: Sildenafil (Revatio®) Formulations Approved to treat Pulmonary Arterial Hypertension (PAH) in adults to improve exercise ability and delay worsening of disease

o Tablets o Oral suspension -- Both oral formulations: 5 or 20 mg, t.i.d. o Injection (clear colorless solution) -- 2.5 or 10 mg, iv for those unable to take orally

Contraceptives Government & Law Texas current events

o Texas legislature made major budget cuts to the women's health budget in 2011 o More than 80 health centers (~25%) have closed or stopped providing preventive women's health services since -- None of these centers funded abortion

Menstrual disorders Dysmenorrhea Non-pharmacologic treatment

o Topical heat therapy (as effective as ibuprofen) o Exercise o Low-fat vegetarian diet o Powdered ginger 250mg PO q6h beginning at onset of menses

PCOS Diagnosis

o Two of three following criteria are met: -- Androgen excess -- Hirsutism, acne, androgenic alopecia -- Testosterone (T) levels -- Ovulatory dysfunction (amenorrhea or oligomenorrhea) -- Polycystic ovaries (ultrasound) o Differential diagnosis -- Thyroid disease (TSH) -- Hyperprolactinemia (Prolactin) -- Adrenal hyperplasia (cosyntropin stimulation test)

Oral Planned Contraceptives Biphasic or Triphasic

o Two or three different dose-combinations within a 21-day period + 7-day placebo -- Typically same amount (with exception) of ethinyl estradiol + 2 (biphasic) or 3 (triphasic) doses of progestins during each cycle o Aims -- Maximizing anti-ovulatory effects -- Preventing breakthrough bleeding -- Minimizing total exposure to hormones

Female Risk Factor: Ovulatory Dysfunction

o Up to 40% of female infertility - most common o Anovulation -- Ovaries do not release an oocyte during a menstrual cycle o Detailed history needed -- Age of menarche -- Menstrual cycle patterns -- Premenstrual symptoms -- Previous pregnancies o Causes: thyroid dysfunction, hyperprolactinemia, polycystic ovary syndrome (PCOS)

Emergency (Postcoital) Contraceptives Selective PR Modulator (SPRM) Ulipristal (Ella®)

o Use: to prevent pregnancy following unprotected intercourse or a known or suspected contraceptive failure o One tablet (30 mg) within 120 hours (5 days) after unprotected intercourse o More efficacious than progestins

Emergency (Postcoital) Contraceptives Progestins Levonorgestrel

o Use: to prevent pregnancy following unprotected intercourse or a known or suspected contraceptive failure o Plan B® or Next Choice® contains 0.75 mg/tablet -- 1st dose: Within 72 h after unprotected intercourse -- 2nd dose: 12 h after 1st dose o Plan B One-Step® contains 1.5 mg/tablet -- 1st dose: Within 72 h after unprotected intercourse

Emergency contraception Yuzpe method

o Using an OC packet to prevent pregnancy o Dosing -- Depends on OCs used -- Goal: 100 mcg EE + 0.5 mg levonorgestrel each dose -- Take one dose q12h x2 doses -- Within 72 hours of intercourse o Restart hormonal contraceptives the next day o Use backup method for 7 days

Female Infertility: Structural Factors

o Uterine cavity or fallopian tubes -- Endometriosis -- Distal tubal obstruction o Pelvic inflammatory disease

Male Factor Infertility Other conditions

o Varicoceles o Genetic conditions o Pituitary tumors o Erectile dysfunction, retrograde ejaculation, obstruction of vas deferens or epididymis o Antidepressants and antihypertensive o Weight

Aromatase Inhibitors PCOS Treatment Adverse effects

o Vasodilation, IHD, HTN, angina, edema, ↑ LDL o Fatigue, mood disorder, HA, pain, depression o Skin rash o Hot flashes o GI distress, nausea, vomiting o Weakness, arthritis, arthralgia, back pain, ostealgia, osteoporosis o Pharyngitis, dyspnea, increased cough

General Treatment

o Vitamin C o Vitamin E o Folic acid o Zinc o Selenium o L-carnitine

Menstrual disorders Amenorrhea Nonpharmacologic Treatment

o Vitamin D and calcium-rich diets if due to hypoestrogenic states o Reverse cause if due to hypothalamic disorder

Contraceptives Pharmacology Oral Planned Contraceptives Drospirenone Blood Clot Concern

o [4-10-2012] The U.S. Food and Drug Administration (FDA) has concluded that drospirenone-containing birth control pills may be associated with a higher risk for blood clots than other progestin-containing pills. o Angeliq®, Beyaz®, Gianvi®, Ocella®, Safyral®, Yaz®, Yasmin®, Zarah®

Long-Term Considerations

o ↑ Ovarian cancer risk More likely in infertile women Possible increase from medications used o Psychosocial issues Higher rates of depression and anxiety Grief and frustration with multiple cycles Offer couple counseling and social support

Thyroid Dysfunction and Infertility

o ↑ Prevalence of thyroid autoimmunity o Hyperthyroidism -- ↑ SHBG and estradiol -- ↑ LH o Hypothyroidism -- ↓ Androstenedione and estrone clearance -- ↑ Peripheral aromatization -- ↓ Plasma binding activity of SHBG -- Normal LH/FSH

Oral contraceptives Contraception Product Selection Overweight/obese

o ≥30/35 mcg EE recommended by some o Oral contraceptive pill failure by body mass index: point estimates and 95% confidence intervals (Obstet Gynecol 2011; 117(1):33-40)

Sterility

the etiology of infertility is established and there is no possibility for conception

Fecundity

the monthly probability of pregnancy

Benign Prostatic Hyperplasia Anticholinergics

tolteradine fesoterodine

Metformin PCOS Treatment

√ +/- Metformin (adjuvant therapy) o Type 2 diabetes mellitus or impaired glucose tolerance (IGT) who fail lifestyle modification o Second line for menstrual irregularity (not as effective as HC for menstrual cycle regulation) o No evidence of improved live births with or without Clomid

Stage One: Controlled Ovarian Stimulation GnRH agonists

√ GnRH agonists: o Role -- Inhibit endogenous secretion of gonadotropins and allow exogenous gonadotropins for ovulation induction -- Follicular maturation -- Initiated in last week of contraceptives o Leuprolide acetate (Lupron®) √ GnRH antagonists ("short" protocol) o Place in therapy -- Block GnRH receptors decreasing secretion of LH and FSH -- Prevents LH surge and premature luteinization of ovarian follicles o Degarelix (Firmagon®) o Ganirelix (Antagon®) o Cetrorelix (Cetrotide®) √ After starting gonadotropins: 50% of dose

Ovarian Hyperstimulation Syndrome (OHSS) Risk factors -- Younger age -- Low body weight -- History of PCOS

√ Monitoring: vaginal ultrasound, serum estradiol q 1-3 days √ Symptoms develop 1-2 weeks after oocyte retrieval o Mild -- GI symptoms, weight gain o Severe -- Ovarian rupture -- Thromboembolism -- Renal failure -- Adult respiratory distress syndrome

Premenstrual dysphoric disorder (PMDD) Pharmacologic treatment

√ Supplements o B6 50-100 mg daily o Calcium carbonate 1200 mg daily √ SSRIs o First line o 60% effective vs. 30% placebo o Relapse on discontinuation in 50% o Onset of effect: within 2 menstrual cycles o Dose continuously or only during luteal phase o Caution with paroxetine in women who do not use reliable contraception; congenital abnormalities o ADRs: sexual dysfunction, sedation, nausea, diarrhea

Benign Prostatic Hyperplasia Dutasteride-Tamsulosin (Jalyn)

√ Symptomatic management of BPH o Superior to tamsulosin and dutasteride monotherapy in symptom improvement o Higher frequency of adverse effects o Recommended for moderate-to-severe symptomatic BPH, enlarged prostrate, and reduced urine flow rate and at risk for disease progression


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