Medicine SC068: The Woman Needs That Drug: Oral Contraceptives, Drug Affecting Uterine Motility

Question 1

Menstrual cycle revision

Answer 1

Menstrual cycle:
- Early follicular phase: Low Estrogen, Undetectable Progesterone
- Late follicular phase: Peak Estrogen, Undetectable Progesterone
- Mid-luteal phase (after ovulation): Decreased Estrogen, Peak Progesterone

FSH:
- Stimulate Estrogen production + Follicle development in ovary

LH:
- Control Corpus luteum —> Stimulate Progesterone production

GnRH:
- Pulsatile manner —> more frequent during late follicular phase

Question 2

Oral contraceptive

Answer 2

Main purpose:
- Interfere with follicle development + ovulation by preventing normal fluctuation of hormones (e.g. Estrogen surge, LH surge)
- Make use of negative feedback mechanism to inhibit FSH, LH release —> Prevent ovulation
- Produce temporary state of infertility which is reversible
- Other fertility factors: Implantation, Cervical mucus formation

Types:
1. Combined pill (Estrogen-Progestin combination)
2. Mini-pill (Progestin-only pill)

Question 3

Combination of Estrogen + Progestin

Answer 3

One pill containing Estrogen (**Ethinylestradiol (more potent than Estradiol)) + **Progestin taken for a period of 21 consecutive days with a break of 7 days

MOA:
- Source of hormone from pills —> Negative feedback —> Selective inhibition of **Pituitary
- **↓ FSH release —> Development of ovarian follicle
- **↓ LH release —> Prevent ovulation
- Other actions
—> Change in **cervical mucus in uterus (Progesterone)
—> Change motility + secretion in uterus
—> ↓ Conception + implantation (only alter environment for implantation but not interfere with implantation itself)

Advantages:
- 21 days with Estrogen to support endometrial growth (partly suppressed by Progestin component) + 7 days hormone free —> shedding of endometrial lining —> withdrawal bleeding (mimic normal menstrual cycle)
- Ovulation starts after discontinuation of pills (can resume fertility quickly vs POP)
- Very effective (>99% on perfect use)

Disadvantages:
- Not suitable for nursing mother (Estrogen may interfere with ***milk production, small amount of hormones can appear in milk but no evidence that this affect baby)
- Adverse CVS effect, Venous thromboembolism (depending on other predisposing factors e.g. smoking, >35 yo)

Available preparations:
1. ***Monophasic agents
- more common now
- E and P same dose in each pill for the 21-day cycle (more convenient for missed dose)
- Do NOT take double pills for missed dose (will mimic normal estrogen surge —> induce ovulation instead —> continue to take pills as normal + 72 hours additional contraceptive method)

2. Biphasic, Triphasic or Four-phasic agents (older type)
   - two, three or four group of pills containing different amounts of E and/or P in 21-day cycle
   —> reduce **total amount of steroids administered
   —> **resemble more closely estrogen-to-progestin ratios during the menstrual cycle
3. ***Extended cycle combination oral contraceptives
   - 84 days of active pills and 7-days of (1) inactive pills or (2) low-dose estrogen pills
   —> delays menstruation
   —> treatment of menorrhagia, dysmenorrhoea, endometriosis, chronic pelvic pain, anaemia
4. ***Continuous combination oral contraceptives
   - a full year of active pills (no inactive pills)
   - eliminates menstruation
   - ↓ menstrual migraines, endometriosis, acne

(3 cycle package: for Menopausal HRT
- 12 Estradiol (2mg)
- 10 Estradiol (2mg) + Norethisterone (1mg)
- 6 Estradiol (1mg))

SE:
- Weight gain, Edema (mineralocorticoid effect (∵ similar structure))
- Risk of thromboembolism
- Breast, Cervical cancer

Question 4

Progestin-only contraceptive

Answer 4

One pill contain Progestin (Progestogen) taken **continuously for 28 day **without a break (mini-pill)

Depot / Implant: injection of long-acting Progestin as depot (e.g. 140mg Medroxyprogesterone acetate every 3 months) / SC implant (last up to 5-6 years)

MOA:
- Inhibition of **Hypothalamus —> slow frequency of **GnRH pulse generator —> **↓ LH release —> prevent ovulation (no LH surge to trigger ovulation)
- **Thickening of cervical mucus —> ↓ sperm penetration
- ***Endometrial alterations (higher vs COC) —> ↓ implantation

Advantages:
- Suitable for patients where use of Estrogen not appropriate —> ***Nursing mothers to prevent pregnancy
- As effective as COC

Disadvantages:
- Unpredictable **spotting + bleeding: sometimes irregular menstrual cycles (∵ suppression of GnRH + subsequent effect on FSH + LH)
- Spotting + bleeding reduced with time —> may result in **amenorrhoea (menstrual cycle may stop)
- Ovulation and menstrual cycle may **not start quickly after cessation of therapy (few months or longer)
- Risk of decrease **bone mineral density for long-acting progestogen injectable contraceptives

Available preparations:
- progestational agents, progestagens, progestogens, gestagens, gestogens
1. Naturally occurring hormone (Progesterone)

2. 17α-Acetoxyprogesterone derivatives (Pregnane)
   - selective activity very similar to that of progesterone
3. 19-Nortestosterone derivatives (Estrane)
   - exhibit androgenic + other activities
   —> more commonly associated with weight gain
   —> exacerbate acne
   —> aggravate hirsutism
4. 19-Norgestrel derivatives (Gonane)
   - lower androgenic activity relative to the estranes
5. Progestins derived from spironolactone (e.g. drospirenone)
   - anti-mineralocorticoid and anti-androgenic activities

Question 5

Oral postcoital contraceptives / Emergency contraceptives / Morning after contraception

Answer 5

1. Estrogen alone / Progestin alone / Combination
   - effective (~99%) when initiated within **72 hrs after an unprotected act
   - less effective than standard oral contraceptive regimens —> not intended as a regular method of contraception
   - often with **anti-emetics (~40% have N+V)
   - less effective than copper IUD (can be inserted 5-7 days after an unprotected act + after a negative pregnancy test)
2. Ulipristal (Selective progesterone-receptor modulator (~ **Anti-progesterone))
   - prevents progesterone from binding to receptors —> postpones follicular ruptures if given prior to ovulation —> inhibit / delay ovulation
   - may impair implantation
   - effective up to **120 hrs after unprotected intercourse
3. Mifepristone (RU-486, abortion pill)
   - progesterone-receptor modulator

Common formulation:
1. Anlitin: Levonorgestrel (1.5mg)
2. ellaOne: Ulipristal acetate (30mg)

Yuzpe method:
- Estrogen combined with Levonorgestrel
- Pills taken in 2 divided doses
- Each dose must contain Estrogen (100-120 mcg Ethinylestradiol) + Progestin (0.5-0.6mg Levonorgestrel / 1.0-1.2mg Norgestrel)

Question 6

Comparison between 2 emergency contraceptives

Answer 6

Initiation period:
- Progestogen only: Up to 72 hours after unprotected intercourse
- Ulipristal: Up to 120 hours after unprotected intercourse

Failure rate:
- Progestogen only: 2-3%
- Ulipristal: 1-2%

Efficacy versus intake time:
- Progestogen only: Efficacy decreases with time
- Ulipristal: Same efficacy within 120 hours

Side effects:
- Both: Headache, nausea, dizziness, fatigue, dysmenorrhea, abdominal pain, back pain and breast tenderness

Effect on the fetus:
- Progestogen only: No adverse effect
- Ulipristal: Little data

Advice on breastfeeding:
- Progestogen only: No breastfeeding for 8 hours after drug use
- Ulipristal: No breastfeeding for 7 days after drug use

Interaction with hormonal contraceptive pills:
- Progestogen only: Efficacy of hormonal contraception is NOT affected
- Ulipristal: Efficacy of hormonal contraception is reduced

Special precaution:
- Both: Concomitant use of progestogen only and ulipristal acetate within the same cycle is not recommended

Question 7

Hormonal replacement therapy

Answer 7

Menopause:
- Decrease production of female hormones by ovaries (both Estrogen and Progestins)
- Increase bone loss —> fractures (vertebral, hip and wrist)
- Increase plasma cholesterol —> atherosclerotic disease —> CVS risk (heart attack and stroke)
- Postmenopausal syndrome: hot flushes, insomnia etc.

Replacement of hormones —> reduce problems?
- Vasomotor symptoms, osteoporosis, vaginal dryness and urogenital atrophy —> **Positive results
- Reduce cardiovascular diseases —> **Negative results

HRT:
- Conjugated Estrogens and Medroxyprogesterone acetate (MPA) or other progestins (most common)
- Continuous / Cyclic regimen

Clinical studies showed no benefits:
- Small increase in CVS and breast cancer with HRT
- Protective effect for colon cancer and osteoporosis
- Guideline: HRT not recommended for prevention of CVS diseases

Postmenopausal hormonal therapy / Menopausal hormone therapy:
- Women with uterus: Estrogen + Progestin for women with uterus
- Women with hysterectomy + with no endometrial problem: Estrogen alone (low dose and normally <5 years)

Contraindications:
- Existing clotting problem (venous and arterial thrombosis)
- Liver diseases
- Family history of certain cancers (Breast cancer + other hormone dependent cancers)

Side effects:
- Venous thrombosis (risk of PE, MI, stroke; particularly in smokers and with existing risk factors)
- Weight gain (dose-dependent; androgen-like effect of Progestins)
- Nausea
- Headache

Question 8

Drugs affecting uterine motility

Answer 8

Uterine stimulating:
1. Oxytocin
2. Prostaglandins (E + F types)

Uterine relaxing:
1. β2 agonists
2. CCB
3. NSAID

Oxytocin:
- Most widely used uterine stimulant (Pitocin, Syntocinon)
- Induce labour at term (slow IV infusion)
- Augment labor in selected patients with uterine dysfunction
- **Prevent / Control PPH
- Correct uterine hypotonicity after delivery / abortion (IM / IV infusion)
- **Stimulate milk let-down reflex (intranasal spray)

(- Initial dose: 0.5-1 mU/min —> 30-60 min intervals gradually increased in increment of 1-2 mU/min until desired contraction pattern established
- Once desired frequency of contractions reached + labour progressed to 5-6 cm dilation —> dose may be reduced by similar increment)

Prostaglandin:
- **Terminate early and middle pregnancy
- Used in Vaginal Suppository form
- **Induce cervical ripening (important before delivery)
- ***Control persistent PPH secondary to uterine atony (lack of normal uterine tone or strength)
- NB in early pregnancy
—> Uterus minimum response to oxytocin
—> Uterus full response to prostaglandin E + F

β2 agonists:
- Tocolytics
- Activate β2 receptor of smooth muscle —> uterine relaxation
- Inhibit uterine contractions —> delay labour
- Delay premature labour
- e.g. Ritodrine (voluntarily withdrawal from US market), Terbutaline (as off-label use in US)

CCB:
- e.g. Nifedipine
- Interfere intracellular Ca homeostasis —> prevent contraction

NSAID:
- e.g. Indomethacin, Ketorolac, Sulindac
- Prostaglandin inhibitor

Question 9

Common preparations of contraceptives / hormonal therapy in QMH

Answer 9

Contraceptive:
1. Yasmin (ethinylestradiol 30ug + drospirenone 3mg)
2. Harmonet (ethinylestradiol 20ug + gestodene 75ug)
3. Microgynon 30ED (ethinylestradiol 30ug + levonorgestrel 75ug)
—> 28 days (21 days fixed combination + 7 rest days)

Postmenopausal HRT:
1. Premarin (0.3 / 0.625mg conjugated estrogens)
2. Premelle (0.625 conjugated estrogen + 2.5mg medroxyprogesterone)