Pharmacotherapy II - Menstruation-Related Disorders

What is cramping pelvic pain occurring with or just prior to menses​

Pathophysiology​?

Primary Dysmenorrhea

What is the pathophysiology of primary dysmenorrhea?

- Release of prostaglandins​

- Possible vasopressin-mediated vasoconstriction​

What are clinical features of primary dysmenorrhea?

- Usually first 1-3 days of cycle​

- Spasmodic, crampy pain, sometimes radiating to back and thighs​

- HA, diarrhea, fatigue, nausea, flushing common​

- Normal pelvic exam

What is the treatment for primary dysmenorrhea? (hint 1st, 2nd, 3rd)

- Non-pharmacologic therapy​: topical heat, exercise​

- 1st Line Treatment choice: NSAIDs​

- 2nd Treatment choice: Oral Contraceptives​

- 3rd Treatment choice: Medroxyprogesterone acetate (MPA) (DepoProvera®) or Levonorgestrel IUD (Mirena®)

Are opioids indicated in primary dysmenorrhea?

NO

Why do NSAIDs work for primary dysmenorrhea?

Beneficial effects due to prostaglandin inhibition, all NSAIDs are probably equally efficacious

What NSAIDs are used for dysmenorrhea?

Ibuprofen (Advil®), Naproxen (Aleve®), Mefenamic acid (Ponstel®), Celecoxib (Celebrex)

What is a possible way to increase effectiveness of NSAIDs for dysmenorrhea?

Begin NSAID therapy at the start of menses or the day prior to menses & continue treatment with scheduled doses (instead of waiting until the onset of symptoms & PRN dosing) -see notes for example dosing

How do oral contraceptives work for dysmenorrhea?

↓ symptoms of dysmenorrhea by inhibiting the proliferation of endometrial tissue, leading to ↓ endometrial prostaglandins = decreased cramping and decreased blood flow

What are unacceptable health risks for estrogen-containing OCPs?

- Age >35 years and smoking > 15 cigarettes p day​

- Multiple risk factors for ASCVD (older age, smoking, DM, HTN)​

Hypertension (>160 mmHg systolic or > 100 diastolic)​

- History or current DVT/PE​

- History of CVA or IHD​

- Current breast cancer​

- Severe cirrhosis​

- Migraine with aura​

- DM >20 years or significant complications (neuropathy, nephropathy)​

How do POPs work for dyamenorrhea?

Induce endometrial atrophy that leads to relief of dysmenorrhea

What is the MoA of Depo-Provera?

Inhibits secretion of gonadotropins which prevents follicular maturation and ovulation and results in endometrial thinning​

What are adverse effects of Depo-Provera?

- Irregular bleeding (spotting)

- Hot flashes

- Weight gain

- Nausea​

What is an adverse effect of Levonorgestrel IUD (Mirena®, Liletta®, Kyleena®)​?

Irregular bleeding

What kind of IUD leads to increased dysmenorrhea/cramping​?

Copper IUD

What are progestin-only pill RED drugs?

Norethindrone 0.35 mg tablets and drospirenone (Slynd) 4 mg tablets

What drug has a similar anti-mineralocorticoid activity as spironolactone; K-sparing, and risk for hyperkalemia?

Drospirenone

What term describes heavy menses or prolonged bleeding​?

Menorrhagia

What is the first line treatment for menorrhegia?

Oral contraceptives or hormonal IUD

What is the progesterone tehrapy treatment for menorrhagia?

PO medroxyprogesterone (Provera®) during luteal phase of menstrual cycle or for 21 days starting on day 5 of the cycle​

What is the acute and nonacute dosing of progesterone therapy for menorrhagia?

Acute: 20 mg TID x 7 days (off label)​

Nonacute: 5-20 mg/day, use lowest effective dose​

What drug can be taken during menses to decreases menstrual blood loss?

NSAIDS

What surgical methods can be used to treat menorrhagia>

Ablation, hysterectomy

What is the MoA of transexamic acid (TXA) in treatment menorrhagia?

Forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin​

What is the dosing of TXA?

1.3 g TID for up to 5 days, works within 2-3 hours ​

What are adverse effects of TXA?

Nausea, dizziness, HA

What are endometriosis treatment options designed to do?

Inhibit ovulation & lower hormone levels, preventing cyclic stimulation of endometrial implants, other options to decrease pain​

What are treatment options for mild to moderate endometriosis?

- NSAIDs​

- Danazol (not common due to AE)​

- Combination OCs

What are treatment options for severe endometriosis?

- GnRH analogs (Lueprolide, Lupron)​

- IM medroxyprogesterone

How do OCPs work for endometriosis?

Prolonged suppression of ovulation will often inhibit further stimulation of residual endometriosis, more effective for severe if taken after one of the other therapies (like GnRH agonists)

What regimen of OCPs is commonly used for endometriosis?

Extended use regimens

What is the MoA of Danazol?

Suppresses output of LH & FSH; causes regression/atrophy of normal & ectopic endometrial tissue

What are adverse effects of Danazol?

- Cardio: edema, hypertension​

- CNS: emotional lability​

- Derm: acne, hair loss or hirsutism, rash, SJS​

- Metabolic: amenorrhea, glucose intolerance, libido changes​

- Hepatic: ↑LFTs​

- Neuromuscular: joint pain

How does leuprolide work for endometriosis?

Chronic administration suppresses ovarian steroidogenesis- estrogen reduced to postmenopausal levels

What are adverse effects of leuprolide?

- Hot flashes, decreased libido, breast changes, amenorrhea, vaginitis, acne​

- Headache, depression, emotional lability, bone loss

What is the monitoring for leuprolide?

- Bone density changes-due to hypoestrogen state​

- Exclude pregnancy prior to initiation

What is a combination of mood disturbance & physical symptoms occurring prior to menses & resolving with the initiation of menses?

PMS

What is premenstrual distress with deterioration in functioning occurring during the 2 weeks preceding menses​

Same symptoms as PMS, but increased severity- interfering with functioning (social, occupational)?

PMDD

When are SSRIs given for PMS and PMDD?

Given continuously or during the luteal phase of the menstrual cycle (initiated at the time of ovulation & discontinued at the onset of menses)

What is the RED drug for SSRIs for PMDD?

Fluoxetine (Sarafem®): 20 mg/day continuously, or 20 mg/day starting 14 days prior to menstruation through first full day of menses (repeat with each cycle)

What are adverse effects of Fluoxetine?

N/HA/insomnia/decreased libido/sexual dysfunction

Beneficial effects often seen in first cycle, try second SSRI in non-responders or switch to daily vs. luteal phase therapy

What monophasic OCP has been shown to be effective for some symptoms associated with PMDD?

Ethinyl estradiol/drospirenone (Yaz, Yasmin)

What PMDD treatment option is saved for severe symptoms or those who cannot tolerate COCs and imrpoves premenstrual emotional symptoms & some physical symptoms?

GnRH agonists

What is an OTC combination product for PMS/PMDD?

Midol ®: APAP/Caffeine/ Pyrilamine maleate

What is a diuretic for treatment of PMS/PMDD that relives breast tenderness and fluid retention and is given during the luteal phase?

Spironolactone

What are adverse effects of spironolactone?

- Hyperkalemia

- Dyspepsia

- Nausea

- Gynecomastia

- Menstrual irregularities

What are 3 other treatments for PMS//PMDD?

- NSAIDs

- GnRH agonist

- Danazol

Patient education for PMS/PMDD management

- Symptom diary​

- Rest​

- Exercise​

- Diet

What are treatment options for psychologic symptoms?

- SSRIs

- TCAs (maybe)

What is a treatment option for bloating?

Spironolactone

What are treatment options for headaches?

Analgesics, NSAIDs

What are treatment options for fatigue and insomnia?

Good sleep hygiene, ↓ caffeine

What menstural cycle altering agent improves mastalgia & may improve other PMS symptoms?

Danazol

What menstrual cycle altering agent suppresses ovulation, has hypoestrogenic effects, and has increased risk of osteoporosis with use > 6 months?

GnRH Agonists (Lupron)

What hormone may relive premenstrual migraine when given in the luteal phase but must be continuously for overall symptom management?

Estrogen

What drugs may cause PMS symptoms?

Cyclic progresterone and Medroxyprogresterone acetate (DepoProvera®