Pregnancy and Lactation: Therapeutic

considerations

Dr. Khaled Alakhali PhD

Learning Outcomes
✓ At the end of the lecture, students should be able to:
✓ Understand the physiology of the pregnancy.
✓ Understand the concepts of pharmacokinetics during
pregnancy.
✓ Understand the treatment guidelines in the pregnant
women.
✓ Know to interpret the prescription for pregnant women.

2
Introduction
✓ Physiologic changes during pregnancy result in changes in
absorption, protein binding, distribution, and elimination.

✓ Altered drug pharmacokinetics during pregnancy can influence

drug selection and dosing.

✓ Drug-induced teratogenicity is a serious concern during

pregnancy, most drugs required by pregnant women can be
used safely.

✓ Clinical pharmacist has a major role in minimizing the ADR

3
Physiology of pregnancy
✓ Fertilization occurs when a sperm attaches to a receptor on
the outer protein layer of the egg.

✓ 6 days after fertilization, the cell mass is termed a blastocyst.

✓ After 6 days of this growth, the blastocyst lies implanted under

the surface of the endometrium and begins to receive
nutrition from maternal blood (embryo).

✓ The embryonic period lasts from approximately 2 weeks after

fertilization until 8 weeks after fertilization. Most body
structures are formed during the embryonic period

4
Pregnancy dating
✓ Approximately 280 days (about 36 to 40 weeks) from the
first day of the last menstrual period to birth.

✓ Pregnancy is divided into three periods of 3 calendar

months, and each period of 3 months is called a trimester.

5
Pregnancy signs and symptoms
✓ Fatigue and increased frequency of urination

✓ Approx 6 weeks’ gestation, the pregnant woman may

experience nausea and vomiting.

✓ Nausea and vomiting usually resolve at 12 to 18 weeks’

✓ Fetal movement is detected in the woman’s lower abdomen at

16 to 20 weeks of gestation.

✓ Changes in consistency of the cervical mucus.

6
Maternal pharmacokinetic changes in
pregnancy
✓ Physiologic changes begin in the first trimester and peak
during the second trimester.

✓ During pregnancy, maternal plasma volume, cardiac

output, and glomerular filtration increase by 30% to 50%,
potentially lowering the concentration of renally cleared
drugs.

✓ Glomerular filtration rate increased 50 % in 1. trimester,

80 % in 2. trimester.

7
Maternal pharmacokinetic changes in
pregnancy
✓ Body fat increases, Plasma albumin concentration decreases

✓ Unbound drugs are more rapidly cleared by the liver and

kidney during pregnancy

✓ Increase in gastric pH may affect the absorption of weak acids

and bases

8
Maternal pharmacokinetic changes in
pregnancy
✓ Higher levels of estrogen and progesterone alter liver enzyme
activity and increase the elimination of some drugs but result
in accumulation of others.

✓ The increased glomerular filtration rate during pregnancy

alters renal excretion of drugs such as penicillin G, digoxin,
aminoglycosides, cephalosporins, sulfonamides, and lithium. This
leads to shorter half life, that often is not clinically significant.

✓ Hepatic clearance and metabolism of drugs is also influenced

by the elevated levels of steroid hormones in the pregnant
women, which may stimulate hepatic microsomal enzyme
activity.

9
Transplacental drug transfer

✓ Most drugs move from the maternal circulation to the fetal

circulation by diffusion.

✓ Drugs with molecular weights less than 500 Da readily cross

the placenta, whereas larger molecules (600–1,000 Da) cross
more slowly, such as insulin and heparin. Lipophilic drugs
crosses more easily than hydrophilic drugs.

✓ Maternal plasma albumin decreases while fetal albumin

increases during the course of pregnancy, which may result in
higher concentrations of certain protein-bound drugs in the
fetus.

✓ Fetal pH is slightly more acidic than maternal pH, permitting

weak bases to more easily cross the placenta.
10
Drug selection during pregnancy
✓ In the period from 18 to 60 days post conception, developing
and teratogenic exposures may result in structural anomalies.

✓ In the pregnancy, exposure to teratogenic agents may result in

retardation of growth, central nervous system abnormalities,
or death.

11
General recommendations for use of
medications in pregnancy
✓ Neural tube defects, cleft palate and lip, and cardiac anomalies
are the most common major congenital anomalies.

✓ Folic acid intake should be encouraged throughout a woman’s

reproductive years.

✓ For women at low risk, folic acid 400 mcg/day is

recommended.

✓ Higher doses of folic acid should not be achieved by taking

multivitamins because of risk for vitamin A toxicity.

✓ Smoking is associated with preterm birth, low birth weight,

and other adverse outcomes.

12
 Neural tube defects

cleft palate and lip

13
Medications are grouped into 1 of 5 categories based on the potential
for producing birth defects. The categories are A, B, C, D and X.
Drugs that fall into either class A or B are considered safe and are
routinely
Category A Controlled studies in pregnant women fail
to demonstrate a risk to the fetus in the
first trimester
Category B Presumed safety based on animal studies,
with no controlled studies in pregnant
women,
Category C Studies in women and animals are not
available. Drugs should be given only if the
potential benefits justify the potential risk
to the fetus.
Category D There is positive evidence of human fetal
risk (unsafe), however in some cases such
as a life-threatening illness the potential
risk may be justified if there are no other
alternatives.
Category X Highly unsafe: risk of use outweighs any
potential benefit. Drugs in this category
14 are contraindicated in women who are or
may become pregnant.
Pregnancy-influenced issues

Gastrointestinal tract Gestational diabetes

✓ Constipation Hypertension

✓ Gastro esophageal reflux Thyroid abnormalities

✓ Hemorrhoids Thromboembolism

✓ Nausea & Vomiting

15
Therapy (Constipation)

Non-Pharmacological Pharmacological

✓ Education ✓ Stool softener

✓ Physical exercise ✓ Lactulose sorbitol, and
✓ Increased intake of dietary ✓ Bisacodyl, can be used but
fiber and fluid reserve it.
✓ Senna (occasionally)
✓ Use of supplemental fiber ✓ Castor oil and mineral oil
should be avoided.

16
Therapy (Gastroesophageal reflux)
Non-Pharmacological Pharmacological

Lifestyle and dietary ✓ Aluminum, Calcium, or

modifications Magnesium antacid
e.g; small, frequent meals; preparations; Sucralfate,
alcohol and tobacco avoidance; ✓ Ranitidine and cimetidine.
food avoidance prior to ✓ Famotidine and
bedtime; elevation of the head Nizatidine(limited use)
of the bed. ✓ If no response to above; use
Metoclopramide,
Omeprazole, and
Lansoprazole

17
Therapy (Nausea and Vomiting)

Lifestyle modifications
e.g; small, frequent meals;
Multivitamins, pyridoxine (vitamin B6),
Shorter work days; food avoidance and cyanocobalamin (vitamin B12),
prior to bedtime; Phenothiazines and Metoclopramide
elevation of the head of the bed.

Ginger has shown efficacy for

hyperemesis

18
Gestational diabetes
✓ American Diabetes Association recommends screening at her
first prenatal visit any woman who has risk factors for
developing gestational diabetes mellitus (e.g., obesity, history of
the condition, glycosuria, or strong family history of diabetes)
✓ If this screening is normal, testing should be repeated between
weeks 24 and 28 of gestation.

✓ To be considered low risk, a woman must fulfill all the

following criteria:
1. Age younger than 25 years,
2. Normal body weight,
3. No known diabetes in first degree relatives,
4. No history of abnormal glucose tolerance,
5. No history of adverse obstetric results

19
20
Normal glucose level
✓ FBG concentration ≤105 mg/dL,
✓ 1-hour postprandial plasma glucose concentration ≤155 mg/dL,
✓ or 2-hour postprandial plasma glucose concentration ≤130
mg/dL

Therapy of gestational diabetes

Non-Pharmacological Pharmacological

Nutritional interventions for all Insulin therapy (recombinant human),

women and caloric restriction for Glyburide, Metformin
obese women, self-monitoring of
blood glucose

21
hypertension
✓ Pregnancy-induced hypertension defined as hypertension
without proteinuria

✓ Preeclampsia (hypertension with proteinuria), and chronic

hypertension (hypertension diagnosed prior to pregnancy with
or without preeclampsia)

✓ Systolic BP 140–169 or diastolic BP 90–109 mm Hg, more than

this value high BP 160/110 mmHg

✓ Calcium supplementation may help prevent hypertension in

pregnancy.

22
Therapy (GHTN)

Non-Pharmacological Pharmacological

Activity restriction, psychosocial ✓Supplemental calcium 1 g/day

therapy, and biofeedback. ✓Low-dose aspirin therapy
(decrease the risk of preeclampsia
by 19%)
✓Labetalol, methyldopa, and
calcium channel blockers.
✓Agents to avoid include:
magnesium sulfate (recommended
in eclampsia) high-dose diazoxide,
nimodipine, chlorpromazine and
ACEI .

23
Thyroid abnormalities
✓ Pregnancy may stimulate the thyroid gland because the structure of
human chorionic gonadotropin is similar to that of thyrotropin

✓ Within 1 to 4 months postpartum, about 4% of women may

experience transient thyrotoxicosis due to extreme secretion of
thyroid hormone.

✓ β-blockers (propranolol or labetalol) can be provided for

symptomatic relief.

✓ 2% to 5% of women develop hypothyroidism between 4 and 8

months after delivery, and levothyroxine replacement used for 6 to
12 months.

24
Therapy of UTI
✓ Amoxicillin can be used if it is not resistant

✓ Cephalexin is considered safe and effective.

✓ Nitrofurantoin should not be used after week 37 due to

concern for hemolytic anemia in the newborn

✓ Sulfa & trimethoprim-contraindicated.

✓ Courses of 7 to 10 days are common, but some studies have

demonstrated that shorter courses of 3 days may be sufficient

25
Acute care issues in pregnancy
(urinary tract infection)
✓ 20-40 % of pregnant women with asymptomatic bacteriuria
develop pyelonephritis later in pregnancy

✓ Pyelonephritis may lead to complications such as premature

delivery, low infant birth weight, fetal death, preeclampsia,
anemia, thrombocytopenia, and transient renal failure.

✓ In 95% of cases, Escherichia coli is the principal infecting

organism.

✓ Others Proteus mirabilis, Klebsiella pneumoniae, Group B

Streptococcus
26
Sexually transmitted diseases (STD)
✓ STD in pregnant women range from infections that may
be transmitted across the placenta and infect the infant
prenatally (e.g., syphilis)
✓ Organisms that may be transmitted during birth and
cause neonatal infection (e.g., Chlamydia trachomatis,
Neisseria gonorrhoeae, or herpes simplex virus)
Syphilis
✓ Penicillin is the drug of choice and is effective in
preventing transmission to the fetus and in treating the
fetus.

27
Recommended Regimens for Treatment of Cervical
Infections Due to Chlamydia in Pregnancy
First-line treatment
✓ Azithromycin 1 g orally in a single dose or
✓ Amoxicillin 500 mg orally three times daily for 7 days
Alternative regimens
✓ Erythromycin base 500 mg orally four times per day for 7 days
or
✓ Erythromycin base 250 mg orally four times per day for 14
days
✓ Erythromycin ethyl succinate 800 mg orally four times per day
for 7 days or
✓ Erythromycin ethylsuccinate 400 mg orally four times per day
for 14 days

28
Headache
✓ Headaches in pregnant women can be classified as primary
(tension, migraine) or secondary (trauma, infection).

✓ Rest, reassurance, and ice packs should be used to initially

treat migraine attacks.

✓ Acetaminophen (with or without codeine).

✓ Non-steroidal anti-inflammatory drugs are considered safe

during the first trimester but are generally contraindicated in
late pregnancy.

29
Allergic rhinitis
✓ Avoidance of allergens, immunotherapy.

✓ Intranasal corticosteroids are the most effective treatment for

allergic rhinitis during pregnancy.

✓ Nasal cromolyn and antihistamines (chlorpheniramine,

tripelennamine, and hydroxyzine) are also considered first-line
choices.

✓ Loratadine and cetirizine can be used but no safety data.

30
Cervical ripening and labor induction
✓ Bishop scoring system, which is based on five parameters:
cervical dilation, cervical effacement (thinning), station of the
baby’s head, consistency of the cervix, and position of the
cervix.
Therapy
✓ A number of non-pharmacologic methods are used for
cervical ripening. Castor oil, hot baths, sexual intercourse, and
nipple stimulation all have been recommended for labor
induction. Herbal supplements.
✓ Prostaglandin E2 and oxytocin is the most commonly used
agent for labor induction after cervical ripening
✓ Methergine also widely used.

31
Medication in breast feeding mothers
✓ Avoid drug therapy when possible.
✓ Use topical therapy when possible.
✓ Medications that are safe for use directly in an infant of the
nursing infant's age are generally safe for the breast-feeding
mother.
✓ Medications that are safe in pregnancy are not always safe in
breast-feeding mothers.
Medication selection
✓ Choose medications with the shortest half-life and highest
protein-binding ability.
✓ Choose medications that are well-studied in infants.
✓ Choose medications with the poorest oral absorption.
✓ Choose medications with the lowest lipid solubility.

32
Medication dosing
✓ Administering single daily-dose medications just before the
longest sleep interval for the infant, usually after the bed-time
feeding.
✓ Breast-feeding infant immediately before medication dose
when multiple daily doses are needed
Medications Not to Be Used in Breast-Feeding Mothers
✓ Antineoplastic agents
✓ Ergotamine tartrate
✓ Bromocriptine
✓ Lithium
✓ Cyclophosphamide
✓ Methotrexate
✓ Cyclosporine
✓ Radiopharmaceuticals

33
Case Study 1
✓ A 30-year-old woman comes to your office after a positive
urine pregnancy test.You collect the following data:
✓ Estimated Gestational Age: 5 weeks, regular menstrual cycles
of 28 days
✓ PMH: Bipolar disorder, hypothyroidism, one spontaneous
abortion
✓ FH: Diabetes, hypothyroidism, hypercholesterolemia
✓ SH: Unemployed; cigarettes, one-half pack daily; no alcohol or
illicit substances
✓ Meds: Lithium 900 mg orally at bedtime; quetiapine 50 mg
orally at bedtime; levothyroxine 50 mcg orally in the morning;
all discontinued 1 week ago

34
Case Study 1
✓ Allergy: Dust mites
✓ ROS: Morning nausea; tiredness
✓ VS: Wt 198 lb (90 kg)/Ht 63 in (160 cm), BP 110/72 mm Hg, P
70 beats/min, RR 12 breaths/min; slight enlargement of thyroid
Questions
✓ How will you confirm gestational age?
✓ What prenatal work up would you perform at this time?
✓ What is the appropriate counseling at this time?
✓ What are the risks of drugs taken in the first weeks of
pregnancy? What resources will you use to find the
appropriate information?
✓ What do you recommend for her pharmacologic treatment?

35
Case Study 2
✓ At 35 weeks’ gestation, the patient is admitted for preterm
labor.
✓ Meds: Lithium 600 mg orally in the morning and at bedtime;
quetiapine 100 mg orally at bedtime; levothyroxine 75 mcg
orally in the morning; insulin NPH 16 units subcutaneously at
bedtime; Insulin aspart 20 units subcutaneously before
breakfast
Questions
✓ Will you recommend a tocolytic agent?
✓ If labor progresses, what special care should be provided?

36
Reference
✓ Pharmacotherapy-By Joseph T.Diprio,9th edition.
✓ Pharmacotherapy A Pathophysiologic Approach-by
Joseph-T.Diprio 9th Edition.
✓ Pharmacotherapy Principles & Practice 4th edition
Marie A. Chisholm, Joseph-T. Diprio

37
Hormone therapy in Women

Dr. Khaled Alakhali PhD

Learning Outcomes
✓ At the end of the lecture, students should be able to:

✓ Knowing about the menopause and pathophysiology

✓ Knowing about the clinical presentation of the menopause.

✓ Describe the diagnosis of the menopause.

✓ Describe the hormone replacement therapy and the treatment

the menopause and hypothyroidism.

✓ Describe the guidelines to aid general practitioners and

gynecologists when prescribing HRT in menopausal women

2
Hormone therapy in Women
✓ Menopause refers to the period of a woman’s life during
which there is a cessation of cyclic menstruation.

Pathophysiology
✓ Pathophysiologic changes associated with menopause are
caused by loss of ovarian follicular activity.

✓ The postmenopausal ovary is no longer the primary site

of estradiol or progesterone synthesis.

3
Hormone therapy in Women
✓ As women age, circulating FSH progressively rises and ovarian
inhibin declines.

✓ When ovarian function has ceased, serum FSH concentrations

are greater than 40 international units/L.

✓ Menopause is characterized by a 10 to 15 fold increase in

circulating FSH concentrations compared with concentrations
of FSH in the follicular phase, a four to five fold increase in
luteinizing hormone, and a greater than 90% decrease in
circulating estradiol concentrations.

4
Clinical Presentation
Menopause is characterized by:
✓ Irregular menses
✓ Increased sweating
✓ Hot flashes
✓ Heat intolerance
✓ Headaches
✓ Irritability
✓ Loss of libido
✓ Vaginal and mammary atrophy, and
✓ Mood swings.

5
Clinical Presentation
✓ Many of these symptoms can be attributed to the loss of the
normal cyclic production of estrogen and progestogen by the
ovaries.

✓ Thus, hormone replacement therapy (HRT) has emerged as a

solution to prevent these unpleasant symptoms.

✓ HRT is available in topical or systemic formulations.

6
Clinical Presentation
✓ Another important effect of menopause on women’s health is:
✓ Impaired bone metabolism and progressive loss of bone density.

✓ Some studies have estimated the prevalence of osteoporosis in

postmenopausal women to be around 1 in 3 women.

✓ Another important effect of menopause on women is the increased

risk of coronary artery disease.

7
Diagnosis
✓ Menopause is determined after 12 consecutive months of
amenorrhea.

✓ FSH on day 2 or 3 of the menstrual cycle greater than 10 to

12 international units/L suggests presence of perimenopause.

✓ The diagnosis of menopause should include:

✓ A comprehensive medical history
✓ Physical examination
✓ Complete blood count, and
✓ Measurement of serum FSH.

8
Diagnosis
✓ When ovarian function has ceased, serum FSH
concentrations exceed 40 international units/L.

✓ Altered thyroid function and pregnancy must be

excluded.

9
Hormone Replacement Therapy
✓ Hormone replacement is the administration of synthetic
estrogen and progesterone to replace depleting levels of
hormones in menopausal women.

Forms and Application of HRT

✓ Estrogen-containing methods
✓ Combined estrogen and progesterone methods
✓ Selective estrogen receptor modulators (SERM)
(Bazedoxifene)
✓ Gonad-mimetics (Tibolone)

10
Hormone Replacement Therapy
Hormones can be prescribed via:

✓ Local methods (hormone-based creams, pessaries, and rings)

✓ Systemic therapy (oral formulations, transdermal patches or gel,

and implants)

✓ Hormones can also be grouped by schedules of

administration, including those taken daily or via cyclic schedules,
such as for progesterone-containing methods.

11
Hormone Replacement Therapy
Indications:

✓ The 3 main indications for the prescription of HRT in

menopausal women are:

✓ To relieve vasomotor symptoms of hot flashes, sweating, and

palpitations

✓ To improve urogenital symptoms of dyspareunia, urinary

frequency, and urinary urgency

✓ To prevent osteoporosis

12
Hormone Replacement Therapy
✓ It is important to understand that HRT has
been statistically proven to only prevent the initial
development of osteoporosis.

✓ Thus, therapy is only effective if started during the first 5

years after menopause.

✓ HRT is therefore indicated for women with low bone

mineral density or a history of osteoporotic fractures.
13
Hormone Replacement Therapy
Contraindications
✓ There are no absolute contraindications to HRT.
Relative contraindications include:
✓ Previous history of breast cancer or endometrial cancer
✓ Porphyria
✓ Severe active liver disease
✓ Hypertriglyceridemia
✓ Undiagnosed vaginal bleeding
✓ Endometriosis
✓ Fibroids
✓ Thromboembolic disease

14
Hormone Replacement Therapy
✓ HRT also has some important side effects that women should
be aware of:-
✓ Nausea, bloating
✓ Fluid retention, and
✓ Mood swings are common.
✓ Weight gain after starting HRT is controversial.

✓ Because of these risks, baseline laboratory and imaging studies

should be performed before commencing HRT.

✓ These investigations can include

✓ Fasting lipid profile
✓ Blood sugar levels
✓ Ultrasonography to assess endometrial thickness and the ovaries
✓ Electrocardiography
✓ Papanicolaou test, and
✓ Mammogram.
15
Hormone Replacement Therapy
Forms
✓ HRT can contain estrogen alone or have a combination of an
estrogen and a progestin.

✓ The most commonly used estrogens are equine estrogen,

micronized 17-beta-estradiol, and ethinyl estradiol.

✓ The most commonly used progestins are

medroxyprogesterone acetate and norethindrone acetate.

✓ The usual dose used in combined therapy is 0.625 mg of

equine estrogen, combined with 2.5 mg of
medroxyprogesterone acetate.
16
Hormone Replacement Therapy
✓ Women who have had a hysterectomy should receive
estrogen alone.

✓ The rationale behind adding progestin to the regimen is

to oppose the effects of the estrogen on the
endometrium, as this can be associated with an increased
risk of carcinogenesis.

✓ Women who have undergone a hysterectomy do not

need the opposing effects of progestin.
17
Hormone Replacement Therapy
✓ Postmenopausal women who have an impaired lipid profile or
an increased risk of osteoporosis may benefit from selective
estrogen receptor modulators (SERMs) (Bazedoxifene).
.

✓ Gonad-mimetics: These drugs can mimic the effects of

estrogen or antagonize the effects of estrogen.

✓ They are known to prevent osteoporosis and have fewer

adverse effects compared with conventional hormone
replacement therapy.
18
Hormone Replacement Therapy
Systemic Hormone Replacement
✓ Systemic HRT has been proven to improve the symptoms of
menopause related to vasomotor disturbance.

✓ These symptoms include:

✓ Hot flashes
✓ Sweating, and
✓ Palpitations.

19
Hormone Replacement Therapy
✓ Systemic HRT is also effective in managing the urogenital
symptoms of menopause, such as:
✓ Vaginal dryness
✓ Superficial dyspareunia, and
✓ Urinary frequency or urgency.

✓ Topical estrogen creams can be used to relieve vaginal dryness

and superficial dyspareunia.

✓ Urogenital symptoms usually improve after prolonged and

continuous HRT and are known to recur after stopping the
treatment.

20
Hormone Replacement Therapy
✓ Systemic HRT is also very effective in preventing osteoporosis,
although the strongest protective effect of HRT in this regard
has been shown to occur within the first 5 years after the
onset of menopause.

✓ Premature ovarian failure is also associated with an increased

risk of osteoporosis, and HRT has been proven to significantly
lower this risk.

21
Hormone Replacement Therapy
Guidelines
✓ The United Kingdom’s National Institute for Health and
Clinical Excellence and the International Menopause Society
issued guidelines to aid general practitioners and gynecologists
when prescribing HRT in menopausal women:
✓ HRT is the mainstay treatment for vasomotor symptoms of
menopause.

✓ The best option is combined equine estrogens with

medroxyprogesterone acetate, or equine estrogens with
bazedoxifene (SERM)

22
Hormone Replacement Therapy

✓ The risk of breast cancer is very low when estrogen is used

alone but slightly higher when combined therapy is used.

✓ It should also be explained to women taking HRT that the risk

of cardiovascular disease is not significantly affected.

23
Hormone Replacement Therapy
Oral Estrogen Oral Estrogen- Oral Estrogen-
Progestin Testosterone
Combinations Combinations
• Estrace (estradiol) • Prempro • Esterified estrogen
• Menest (esterified (conjugated equine +
estrogen) estrogen + methyltestosterone
medroxyprogester
• Premarin (conjugated
one)
equine estrogen)
• Prefest (estradiol +
• Cenestin (conjugated
norgestimate)
synthetic estrogen)

24
Case study
✓ A 52-year-old woman with a history of hypertension,
hyperlipidemia, and hypothyroidism presents to the clinic
complaining of hot flashes, vaginal dryness, and insomnia. She
states that she experiences approximately four hot flashes per
day and is awakened from sleep at least two to three times a
week in a “pool of sweat” requiring her to change her clothes
and bed covers. Her symptoms began about 6 months ago, and
over that time, they have worsened to the point where they
have become very bothersome. On questioning, she states her
last menstrual period was 18 months ago.
Questions:
✓ Which of the patient’s symptoms and past medical history are
consistent with menopause?
✓ What additional information do you need to know in order to
make an appropriate therapeutic plan for this patient?

25
Case study
✓ PMH: Hypertension since age 45, currently controlled;
hyperlipidemia, currently controlled; hypothyroidism since age 25,
but symptoms indicative of worsening control; hysterectomy in
2010.
✓ FH: Father: Alive with HTN and CHD (MI at age 60). Mother: Alive
with hypothyroidism, HTN, and GERD. Siblings: Two sisters alive and
well, menopausal with hx of hot flashes.
✓ SH: Occupation: Nurse; non-smoker; drinks one to two glasses of
red wine with dinner on the weekends; denies illicit drug use.
✓ Meds: Lisinopril/HCTZ 20/12.5 mg once daily; simvastatin 40 mg at
bedtime; Synthroid 0.075 mg by mouth once daily; multivitamin by
mouth once daily.
✓ ROS: (+) hot flashes, night sweats, vaginal dryness and itching; (+)
insomnia, bowel changes, 5-lb weight loss since last visit 6 months
ago.
26
Case study
✓ VS: BP 128/78, P 92, RR 16, T 37.0°C (98.6°F), Wt 74.5 kg (164
lb)
✓ HEENT: WNL
✓ Neck: Supple; no adenopathy, no thyromegaly.
✓ Breasts: Supple; no masses
✓ CV: normal S1 and S2; no murmurs
✓ Abd: Soft, nontender, nondistended
✓ Genitourinary: Pelvic examination normal except (+) mucosal
atrophy; (+) hysterectomy
✓ Labs: FSH: 76 mIU/mL (76 IU/L) TSH: 0.3 μIU/mL (0.3 mIU/L)
Chem-7: Na 135 mEq/L (135 mmol/L), K 4.5 mEq/L (4.5
mmol/L), Cl 109 mEq/L (109 mmol/L), CO2 25 mEq/L (25
mmol/L), BUN 9 mg/dL (3.2 mmol/L), SCr 0.9 mg/dL (80
μmol/L), Glucose 98 mg/dL (5.4 mmol/L)

27
Case study
✓ CBC: Hgb 13 g/dL (130 g/L or 8.06 mmol/L), Hct 39%
(0.39 volume fraction), WBC 5.5 × 103/mm3 (5.5 ×
109/L), platelets 234 × 103/mm3(234 × 109/L) Fasting
lipid levels: TC 200 mg/dL (5.17 mmol/L), low-density
lipoprotein (LDL) 126 mg/dL (3.26 mmol/L), high-density
lipoprotein (HDL) 50 mg/dL (1.30 mmol/L), Triglycerides
(TG) 115 mg/dL (1.30 mmol/L)

28
Case study
Questions:
✓ Assess the patient’s condition based on this additional
information.
✓ What are the goals of treatment for this patient?
✓ Assess the patient’s risk factors for heart disease and
breast cancer.
✓ Recommend nonpharmacologic and pharmacologic
treatment for this patient. Justify your recommendations.

29
Case study
✓ The patient has been in good health for the past 7 years.
✓ She reports adherence with her medications, a healthy
diet and exercise routine, and her medical conditions are
controlled. However, 1 month ago she was diagnosed with
stage 2 breast cancer following a routine mammogram.
She is concerned that her hormone therapy may have
caused the breast cancer.
✓ Educate the patient regarding the risk of breast cancer
and hormone therapy.

30
Case study
✓ Based on the information presented, create a care plan
for this patient’s hot flashes and vaginal dryness.
The plan should include:
✓ (a) A statement identifying the problem and its severity
✓ (b) Goals of therapy
✓ (c) A therapeutic plan based on individual patient-specific
factors
✓ (d) Subjective and objective monitoring parameters
✓ (e) A follow-up evaluation to assess for adverse effects
and adherence and to determine whether the goals of
therapy have been achieved
31
Case study
✓ It has been 6 months since this patient completed
chemotherapy and radiation for breast cancer. She
presents to her PCP for follow-up with a chief complaint
of recurrent hot flashes. She also complains of recurrent
vaginal dryness but denies insomnia.
✓ Recommend the most appropriate therapy for her
recurrent hot flashes and vaginal dryness.

32
Reference
✓ Pharmacotherapy-By Joseph T.Diprio,9th edition.
✓ Pharmacotherapy A Pathophysiologic Approach-by
Joseph-T.Diprio 9th Edition.
✓ Pharmacotherapy Principles & Practice 4th edition
Marie A. Chisholm, Joseph-T. Diprio

33
 Contraception

Dr. Khaled Alakhali PhD

Introduction
✓ Contraception is the prevention of pregnancy following sexual
intercourse by inhibiting sperm from reaching a mature ovum.

✓ Method failure is a failure inherent to the proper use of the

contraceptive alone.

✓ User failure takes into account the user’s ability to follow

directions correctly and consistently.

2
The Menstrual Cycle
✓ The median length of the menstrual cycle is 28 days (range 21
to 40).
✓ The first day of menses is day 1 of the follicular phase.
✓ Ovulation usually occurs on day 14 of the menstrual cycle.
✓ After ovulation, the luteal phase lasts until the beginning of the
next cycle.
✓ Epinephrine and norepinephrine stimulate the hypothalamus to
stimulates the anterior pituitary to secrete bursts of
gonadotropins, follicle-stimulating hormone (FSH), and
luteinizing hormone (LH).
✓ In the follicular phase, FSH causes follicles for continued
growth. Between 5 and 7 days, one of these becomes the
dominant follicle, which later ruptures to release the oocyte.

3
The Menstrual Cycle
✓ The dominant follicle develops increasing amounts of estradiol
and inhibin, which cause a negative feedback on the secretion
of FSH.
✓ The dominant follicle continues to grow and synthesizes
estradiol, progesterone, and androgen.
✓ FSH regulates aromatase enzymes that induce conversion of
androgens to estrogens in the follicle.
✓ The pituitary releases a mid-cycle LH surge that stimulates the
final stages of follicular maturation and ovulation.
✓ Ovulation occurs 24 to 36 hours after the estradiol peak and
10 to 16 hours after the LH peak.
✓ The LH surge, occurring 28 to 32 hours before a follicle
ruptures, is the most clinically of ovulation.

4
The Menstrual Cycle
✓ Conception is most successful when intercourse takes place
from 2 days before ovulation to the day of ovulation.

✓ After ovulation, the remaining luteinized follicles become the

corpus luteum, which synthesizes androgen, estrogen, and
progesterone.

✓ If pregnancy occurs, human chorionic gonadotropin prevents

regression of the corpus luteum and stimulates continued
production of estrogen and progesterone.

✓ If pregnancy does not occur, the corpus luteum degenerates,

and progesterone declines. Then menstruation occurs.

5
Treatment
Non-pharmacologic Therapy
A comparison of methods of nonhormonal contraception
✓ Condoms, male
✓ Condoms, female (Reality)
✓ Cervical cap (Fem Cap, Leah’s Shield)
✓ Spermicides alone
✓ Sponge (Today)

Periodic Abstinence
✓ The abstinence (rhythm) method is not well accepted, as
it is associated with relatively high pregnancy rates and
avoidance of intercourse for several days in each cycle.

6
Treatment
Non-pharmacologic Therapy
Barrier Techniques
✓ The effectiveness of the diaphragm depends on a barrier and
on the spermicidal cream or jelly placed in the diaphragm
before insertion.

✓ The cervical cap, can be inserted 6 hours prior to intercourse,

and women should not wear the cap for longer than 48 hours
to reduce the risk of toxic shock syndrome.

✓ Most condoms made of latex rubber, which is not

impermeable to viruses.

✓ Mineral oil–based vaginal drug formulations can decrease

barrier strength of latex by 90% in 60 seconds.

7
Treatment
Non-pharmacologic Therapy
Barrier Techniques
✓ Condoms with spermicides are no longer recommended,
due to no protection against pregnancy or STDs and may
increase to HIV.

✓ The female condom (Reality) covers the labia as well as

the cervix, thus it may be more effective than the male
condom.

8
Pharmacologic Therapy
Spermicides
✓ Spermicides, are surfactants that destroy sperm cell walls.

✓ No protection against STDs, and when used more than two

times daily, also increase the transmission of HIV.

✓ Women at high risk for HIV should not use spermicides.

Spermicide-Implanted Barrier Techniques

✓ The vaginal contraceptive sponge (Today) provides protection
for 24 hours.

✓ After intercourse, the sponge must be left in place for at least

6 hours before removal.
9
Hormonal Contraception
Composition and Formulations
✓ Hormonal contraceptives contain either a combination of
estrogen and progestin or a progestin alone.

✓ Progestins thicken cervical mucus, delay sperm transport, and

induce endometrial atrophy.

✓ Progestins also block the LH surge and thus inhibit ovulation.

✓ Estrogens suppress FSH release, which may contribute to

blocking the LH surge.

10
Hormonal Contraception
Components
✓ Two synthetic estrogens are used in hormonal contraceptives,
ethinyl estradiol (EE) and mestranol.
✓ Mestranol must be converted to EE in the liver to be active. It is
approximately 50% less potent than EE.
✓ Most combined oral contraceptives (OCs) contain estrogen at
doses of 20 to 50 mcg of EE daily.
✓ Progestins vary in activity and differ with respect to inherent
estrogenic, antiestrogenic, and androgenic effects.
✓ Their estrogenic and antiestrogenic properties occur due to
progestins are metabolized to estrogenic substances.
✓ Androgenic properties occur because of the structural similarity of
the progestin to testosterone.

Please refer to any text book for lists available OCs by brand name and hormonal composition.

11
Pharmacologic Therapy
Considerations with Oral Contraceptive Use
✓ Recommendation of the American College of Obstetricians
and Gynecologists is to allow after a medical history and blood
pressure measurement.
✓ Non-contraceptive benefits of OCs include:
✓ Decreased menstrual cramps and ovulation pain
✓ Decreased menstrual blood loss
✓ Improved menstrual regularity
✓ Increased hemoglobin concentration, Improvement in acne
✓ Reduced risk of ovarian and endometrial cancer
✓ Reduced risk of ovarian cysts
✓ Reduced ectopic pregnancy
✓ Reduced pelvic inflammatory disease, and
✓ Reduced benign breast disease.
✓ The transdermal patch may cause less breast discomfort and
dysmenorrhea than OCs.
12
Adverse effects associated with combined
hormonal contraceptives (CHCs)
Estrogen excess
✓ Nausea, breast tenderness, headaches, weight gain,
dysmenorrhea, menorrhagia, and uterine fibroid growth
Estrogen deficiency
✓ Vasomotor symptoms, nervousness, decreased libido.
Progestin excess
✓ Increased appetite, weight gain, bloating, constipation.
✓ Acne, oily skin, hirsutism. depression, fatigue, irritability
Progestin deficiency
✓ Dysmenorrhea, menorrhagia.

The main safety concern about CHCs is their lack of protection

against STDs.

13
Women over 35 Years of Age
✓ CHCs containing less than 50 mcg EE are an acceptable
form of contraception for nonsmoking women up to the
time of menopause.
✓ Increased risk of myocardial infarction or stroke in
healthy, nonsmoking women older than 35 years of age
using low-dose OCs.
Smoking Women:
✓ Women over 35 years who smoke and take OCs have an
increased risk of MI and stroke.
Hypertension:
✓ In women with hypertension, OCs have been associated
with an increased risk of MI and stroke.

14
Women over 35 Years of Age
Diabetes:
✓ Nonsmoking women younger than 35 years with diabetes, but
no vascular disease, can safely use CHCs, but diabetic women
with vascular disease should not use OCs.
Dyslipidemia:
✓ Progestins decrease high-density lipoprotein (HDL) and
increase low-density lipoprotein (LDL).
✓ Estrogens decrease LDL but increase HDL and triglycerides.
Thromboembolism:
✓ Estrogens have development of venous thromboembolism and
pulmonary embolism.

15
Women over 35 Years of Age
Migraine Headache:
✓ Women with migraines may experience a decreased or
increased frequency of migraine headaches when using CHCs.
Breast Cancer:
✓ The WHO precautions state that women with recent personal
history of breast cancer should not use CHCs, but that CHCs
can be considered in women without evidence of disease for 5
years.
Systemic Lupus Erythematosus (SLE):
✓ CHCs should be avoided in women with SLE and
antiphospholipid antibodies. Progestin-only contraceptives can
be used in these women.

16
Choice of an Oral Contraceptive
✓ Adolescents, underweight women 50 kg, women older than 35
years, and those who are perimenopausal may have fewer side
effects with OCs containing 20 to 25 mcg of EE.

✓ Women weighing more than 72.7 kg may have higher

contraceptive failure rates with low-dose OCs and may benefit
from pills containing 35 to 50 mcg of EE.

17
Choice of an Oral Contraceptive
Women with:
✓ Migraine headaches
✓ History of thromboembolic disease
✓ Heart disease
✓ Cerebrovascular disease
✓ SLE with vascular disease, and
✓ Hypertriglyceridemia
✓ They are good candidates for progestin-only methods.

✓ Women older than 35 years who are smokers or are

obese, or hypertension or vascular disease, should use
progesterone-only methods.

18
Managing Side Effects:
✓ Many symptoms occurring in the first cycle of OC use:
✓ Bleeding
✓ Nausea
✓ Bloating
✓ Improve by the second or third cycle of use.

✓ Women should be instructed to immediately discontinue

CHCs if they experience warning signs often called
ACHES (abdominal pain, chest pain, headaches, eye
problems, and severe leg pain).

19
Drug Interactions:
✓ Rifampin reduces the efficacy of OCs.

✓ Case reports have shown a reduction in EE levels when CHCs

are taken with tetracyclines and penicillin derivatives.

✓ Phenobarbital, carbamazepine, and phenytoin reduce efficacy of

OCs, and many anticonvulsants are known teratogens.

✓ The use of condoms in conjunction with high-estrogen OCs

or intrauterine devices (IUDs) may be considered for women
taking these drugs.

Please refer to any text book for drug interaction for lists available OCs and CHCs.

20
Discontinuation of the Oral Contraceptive,
Return of Fertility
✓ Traditionally, women are advised to allow two to three normal
menstrual periods after discontinuing CHCs before becoming
pregnant.
✓ The average delay in ovulation after discontinuing OCs is 1 to
2 weeks

Emergency Contraception
✓ Plan B is the only product FDA approved for EC and is the
regimen of choice. Plan B contains two tablets, each containing
0.75 mg levonorgestrel. The first tablet is to be taken within 72
hours of unprotected intercourse (the sooner, the more
effective); the second dose is taken 12 hours later.

✓ Common side effects of EC are nausea, vomiting, and irregular

bleeding.

21
Transdermal Contraceptives
✓ A combination contraceptive is available as a transdermal
patch, which may have improved adherence compared to OCs.
✓
✓ The patch should be applied to the abdomen, buttocks, upper
torso, or upper arm at the beginning of the menstrual cycle
and replaced every week for 3 weeks.

✓ Preliminary data indicating a higher incidence of

thromboembolic events with the patch.

22
Contraceptive Rings
✓ The first vaginal ring releases 15 mcg/day of EE and 120
mcg/day of etonogestrel over a 3-week period.

✓ On first use, the ring should be inserted on or prior to the

fifth day of the cycle, remain in place for 3 weeks, then be
removed.

✓ One week should lapse before the new ring is inserted on the
same day of the week as it was for the last cycle.

23
Long-Acting Injectable and Implantable
Contraceptives
✓ Women who benefit from progestin-only methods, are those who
are breast-feeding, those who are intolerant to estrogens, and those
with concomitant medical conditions in which estrogen is not
recommended.
✓ Also injectable and implantable contraceptives are beneficial for
women with compliance issues.
Injectable Progestins
✓ DMPA (depot-medroxyprogesterone acetate) 150 mg administered
by deep IM within 5 days of the onset of menstrual bleeding inhibits
ovulation for more than 3 months.
✓ The dose should be repeated every12 weeks to ensure continuous
contraception.
✓ A new formulation contains 104 mg of DMPA, which is injected
subcutaneously into the thigh or abdomen.
24
✓ DMPA can be given immediately postpartum in women
who are not breast-feeding, but in women who are
breast-feeding, it should not be given until 6 weeks
postpartum.

✓ Adverse effect of DMPA is:

✓ Menstrual irregularities
✓ Breast tenderness
✓ Weight gain
✓ Depression
✓ Osteoporosis

25
Subdermal Progestin Implants
✓ Implanon is a single, 4-cm implant (plastic rod), containing 68 mg of
etonogestrel that is placed under the skin of the upper arm.

✓ It releases 60 mcg daily for the first month, decreasing gradually to

30 mcg/daily at the end of the 3 years of recommended use.

✓ With perfect efficacy 100%, but may be less in women weighing

more than 130% of their ideal body weight.

✓ Adverse effect is irregular menstrual bleeding. Other side effects are

headache, vaginitis, weight gain, acne, and breast and abdominal pain.

✓ It is contraindicated in women who are pregnant, have active liver

disease, a history of thromboembolic events, or a history of breast
cancer.

26
Intrauterine Devices
✓ IUDs cause low inflammation and increased prostaglandin
formation.

✓ Endometrial suppression is caused by the progestin-releasing

IUD.

✓ Efficacy rates are greater than 99%.

✓ Pelvic inflammatory disease is highest during the first 20 days

after the insertion procedure.

✓ ParaGard (copper) can be left in place for 10 years. A

disadvantage is increased menstrual blood flow and
dysmenorrhea.

27
Evaluation of Therapeutic Outcomes
✓ Glucose levels should be monitored closely when CHCs are
started in patients with a history of diabetes mellitus.

✓ Contraceptive users should have at least annual screening, and

they should also be regularly evaluated bleeding, amenorrhea,
weight gain, and acne.

✓ Women using DMPA should be evaluated every 3 months for

weight gain, menstrual cycle disturbances, and STD risks.

✓ Patients on DMPA also should be weighed, have their blood

pressure monitored, and have a physical exam, and
Papanicolaou smear annually, as well as mammogram as
indicated based on the patient’s age.

28
Reference
✓ Pharmacotherapy-By Joseph T.Diprio,9th edition.
✓ Pharmacotherapy A Pathophysiologic Approach-by
Joseph-T.Diprio 9th Edition.
✓ Pharmacotherapy Principles & Practice 4th edition
Marie A. Chisholm, Joseph-T. Diprio

29
Menstruation-Related Disorders

Dr. Khaled Alakhali PhD

Learning Outcomes
✓ At the end of the lecture, students should be able to:
✓ Understand the most common menstruation-related disorders.
✓ Understand the pathophysiology of dysmenorrhea.
✓ Understand the clinical presentation, diagnosis and treatment of
dysmenorrhea.
✓ Understand the pathophysiology of amenorrhea.
✓ Understand the clinical presentation, diagnosis and treatment of
amenorrhea
✓ Understand the pathophysiology of anovulatory bleeding.
✓ Understand the clinical presentation, diagnosis and treatment of
anovulatory bleeding
✓ Understand the pathophysiology of menorrhagia.
✓ Understand the clinical presentation, diagnosis and treatment of
menorrhagia.

2
Introduction
✓ The most common menstruation-related disorders include:
✓ Dysmenorrhea
✓ Amenorrhea
✓ Anovulatory bleeding, and
✓ Menorrhagia.

✓ These disorders negatively affect:

✓ Quality of life
✓ Reproductive health
✓ Work productivity, and
✓ May lead to adverse long-term health consequences, such as
osteoporosis or polycystic ovarian syndrome.

3
Dysmenorrhea
✓ Dysmenorrhea is pelvic pain, generally described as
cramping, that occurs during or just prior to
menstruation.

✓ Primary dysmenorrhea is pain in the setting of

normal pelvic anatomy and physiology,

Whereas

✓ Secondary dysmenorrhea is associated with

underlying pelvic pathology.

4
Epidemiology and Etiology
✓ Rates of dysmenorrhea range from 16% to 90%.

✓ Around 8% to 15% of women with dysmenorrhea report

limited daily activities or missed days in work or school.

✓ Risk factors for dysmenorrhea include:

✓ Irregular or heavy menses
✓ Age less than 30 years
✓ Menarche prior to age 12 years
✓ Body mass index (BMI) less than 20 kg/m2
✓ History of sterilization or sexual abuse, and
✓ Smoking.

✓ Causes of secondary dysmenorrhea may include

endometriosis, pelvic inflammatory disease, uterine or cervical
polyps, and uterine fibroids.
5
Pathophysiology
✓ In primary dysmenorrhea, elevated arachidonic acid
levels in the menstrual fluid lead to increased
concentrations of prostaglandins and leukotrienes in
the uterus.

✓ This induces:
✓ Uterine contractions
✓ Stimulating pain fibers
✓ Reducing uterine blood flow and
✓ Causing uterine hypoxia

6
Clinical Presentation and Diagnosis of
Dysmenorrhea
General
✓ Acute distress may be present depending on the severity of
menstrual pain.
Symptoms
✓ Crampy pelvic pain (lasting 1–3 days) beginning shortly before or at
menses onset. Associated symptoms may include nausea, vomiting,
diarrhea, hypertension, and/or tachycardia.
Laboratory Tests
✓ Sexually active females should receive a pelvic examination to screen
for sexually transmitted diseases.
✓ Gonorrhea, chlamydia cultures or PCR, wet mount (vaginal smear).
Other Diagnostic Tests
✓ Pelvic ultrasound may be used to identify anatomic abnormalities
(eg, masses/lesions), ovarian cysts, or endometriomas.
7
Treatment

Desired Outcomes
✓ Desired treatment outcomes are relief of pelvic pain,
improved quality of life, and fewer lost days at school and
work.

8
Nonpharmacologic Therapy
✓ Nonpharmacologic interventions which diminish
dysmenorrhea symptoms include:
✓ Topical heat therapy
✓ Regular exercise
✓ Transcutaneous electric nerve stimulation (TENS), and
✓ Acupuncture.
✓ In addition, a low-fat vegetarian diet has been shown to lessen
the intensity and duration of dysmenorrhea

9
Pharmacologic Therapy

10
Nonsteroidal Anti-inflammatory Drugs
(NSAIDs)
✓ NSAIDs are the treatment of choice for dysmenorrhea.
Mechanism of action
✓ By inhibiting prostaglandin production, they exert
analgesic properties, decrease uterine contractions, and
reduce menstrual blood flow.
✓ Choice of one agent over another is based on cost,
convenience, and patient preference.
✓ Most commonly used agents are naproxen and ibuprofen.
✓ Treatment with an NSAID should begin 1 to 2 days prior
to the start of menses or at the onset of dysmenorrhea
and continued for 2 to 3 days or until pain resolves
11
Combination Hormonal Contraceptives
(CHCs)
✓ CHCs improve mild to severe dysmenorrhea by inhibiting the
proliferation of endometrial tissue and ovulation, thereby
reducing prostaglandin secretion and menstrual blood volume.

✓ Two to three months of therapy are required to achieve the

full effect. Both standard (28-day) and extended cycle (91-day)
therapies are effective for primary dysmenorrhea.

✓ If no response occurs after 3 months of therapy, the patient

should be evaluated for secondary causes

12
Progestin-only Hormonal Contraceptives

✓ These agents diminish dysmenorrhea by reducing or

eliminating menses over time, thus eliminating
prostaglandin release

Three agents are available:

✓ Depot medroxyprogesterone acetate
✓ Etonogestrel implant, and
✓ Levonorgestrel-releasing intrauterine system.

13
Dysmenorrhea in Adolescents
✓ Dysmenorrhea is reported in 60% to 90% of adolescent
females.

✓ It is the most common reason for adolescents to miss school

or work.

✓ One study showed that most young females are treating pelvic
pain with nonpharmacologic therapies, while other studies
showed that many either do not know to use NSAIDs or use
subtherapeutic doses.

✓ Treatment in adolescents includes NSAIDs and oral CHCs are

most common, levonorgestrel IUD use is also an option.

14
Amenorrhea
✓ Amenorrhea is the absence of menses.

✓ Primary amenorrhea occurs prior to age 15 in the

presence of normal secondary sexual development or
within 5 years of thelarche (if occurring before age 10).

✓ Secondary amenorrhea is the absence of menses for

three cycles or 6 months in a previously menstruating
woman

15
Epidemiology and Etiology
✓ Unrecognized pregnancy is the most common cause of
amenorrhea, therefore, a urine pregnancy test should be
one of the first steps in evaluating amenorrhea.

✓ Amenorrhea not related to pregnancy, lactation, or

menopause occurs in 3% to 4% of women.

✓ Additional causes of secondary amenorrhea include

polycystic ovarian syndrome (PCOS), hypothalamic
suppression, hyperprolactinemia, or primary ovarian
insufficiency

16
Pathophysiology
✓ Normal menstrual cycle physiology depends on hormonal
interactions involving the hypothalamus, anterior pituitary
gland, ovary, and endometrium.

✓ Amenorrhea is a potential side effect from using low-dose or

extended oral CHCs and depot medroxyprogesterone acetate.

✓ Many women experience delayed return of menses after CHC

discontinuation.

✓ If spontaneous resolution of amenorrhea does not occur

within 3 to 6 months following CHC discontinuation,
evaluation for other conditions should be considered (eg,
PCOS).

17
Clinical Presentation and Diagnosis of
Amenorrhea
General
✓ Concerns about cessation of menses and fertility implications
Symptoms
✓ Cessation of menses
✓ Possible reports of infertility, vaginal dryness, decreased libido
Signs
✓ Absence of menses by age 15 in the presence of normal
secondary sexual development or within 5 years of thelarche
(if occurs before age 10).
✓ Recent significant weight loss or gain
✓ Presence of acne, hirsutism, hair loss, or acanthosis nigricans
may suggest androgen excess.

18
Clinical Presentation and Diagnosis of
Amenorrhea
Laboratory Tests
✓ Pregnancy test
✓ TSH
✓ Prolactin
✓ If PCOS is suspected, consider free or total testosterone
✓ 17-hydroxyprogesterone, fasting glucose, and fasting lipid panel.
✓ If premature ovarian failure is suspected, consider follicle
stimulating hormone (FSH) and luteinizing hormone (LH)
measurements.
Other Diagnostic Tests
✓ Progesterone
✓ Pelvic ultrasound to evaluate for polycystic ovaries

19
Treatment
Desired Outcomes
Treatment goals include:
✓ Restoring the normal menstrual cycle
✓ Preserving bone density
✓ Preventing bone loss
✓ Improving quality of life, and
✓ Restoring ovulation, thus improving fertility.

✓ Amenorrhea attributable to hypoestrogenism (eg, premature

ovarian insufficiency) can cause hot flashes and dyspareunia.
✓ In prepubertal females, the absence of secondary sexual
characteristics and menarche may occur.

20
✓Nonpharmacologic Therapy
✓ Nonpharmacologic therapy for amenorrhea depends on the
underlying cause.

✓ Amenorrhea secondary to undernutrition or anorexia may

respond to weight gain and psychotherapy.

✓ If excessive exercise is the culprit, exercise reduction is

recommended

21
Pharmacologic Therapy
Estrogen/Progestin Replacement Therapy
✓ For most conditions associated with primary or secondary
amenorrhea estrogen treatment is recommended.

✓ To minimize risk of endometrial hyperplasia and cancer,

progestin should also be given to women with an intact uterus.

✓ Estrogen’s role is to reduce osteoporosis risk, stimulate and

maintain secondary sexual characteristics, and improve quality
of life

22
Pharmacologic Therapy
Dopamine Agonists
✓ In women with hyperprolactinemia who desire conception,
dopamine agonists are an option. Dopamine agonists reduce
prolactin levels and resolve amenorrhea. Additionally, they
restore ovulation in 80% to 90% of women. The most
commonly studied agents are bromocriptine and cabergoline.
Progestins
✓ Progestins have long been used to induce withdrawal bleeding
in women with secondary amenorrhea.
✓ Withdrawal bleeding occurs with intramuscularly injected
progesterone and oral medroxyprogesterone acetate in 70%
and 95% of patients, respectively. The usual dose of
medroxyprogesterone acetate is 10 mg orally once daily for 7
to 10 days
23
Pharmacologic Therapy
Insulin-Sensitizing Agents
✓ Amenorrhea related to anovulation and PCOS may respond to
insulin sensitizing agents. Using metformin for this purpose is
discussed in the anovulatory bleeding section.

✓ All patients experiencing amenorrhea should follow a diet rich

in calcium and vitamin D to support bone health.

✓ Supplemental calcium and vitamin D (1200 mg/800

International Units per day) should be recommended for
patients with inadequate dietary consumption.

24
Amenorrhea in Adolescents
✓ Adolescence is when peak bone mass is achieved.

✓ Estrogen replacement, typically via a CHC, is important.

✓ Recent data suggest that CHCs and depot

medroxyprogesterone acetate may reduce bone mineral density
(BMD) for short term.

✓ CHCs are recommended in the adolescent population.

✓ Ensuring adequate dietary or supplemental calcium and vitamin D

intake in this population is imperative.

25
Anovulatory bleeding
✓ Anovulatory uterine bleeding (AUB) is irregular
menstrual bleeding from the endometrium ranging from
light spotting to heavy blood flow.

✓ AUB includes PCOS, which typically presents with:

✓ Irregular menstrual bleeding
✓ Hirsutism
✓ Obesity, and/or
✓ Infertility

26
Epidemiology and Etiology
✓ Anovulatory uterine bleeding is the most common form of
noncyclic uterine bleeding.

✓ All women of reproductive age should have a pregnancy test

when presenting with irregular menstrual bleeding.

✓ Anovulation results from dysfunction at any level of the

hypothalamic-pituitary-ovarian (HPO) axis which can be due
to physiologic life stages such as:
✓ Adolescence
✓ Perimenopause
✓ Pregnancy, and lactation or
✓ Pathologic causes

27
Epidemiology and Etiology
✓ Anovulation also occurs at any time during the reproductive
years due to a pathologic cause.

✓ The most common causes of nonphysiologic ovulatory

dysfunction are PCOS, hypothalamic amenorrhea,
hyperprolactinemia, and premature ovarian failure.

✓ PCOS, responsible for 55% to 91% of ovulatory dysfunction

cases, occurs in approximately 7% of women

28
Pathophysiology
✓ A normal ovulatory cycle includes:
✓ Follicular development
✓ Ovulation
✓ Corpus luteum development, and
✓ Luteolysis.
✓ During the cycle, the endometrium proliferates and undergoes
secretory changes and desquamation
✓ This is influenced by estrogen alone, then by estrogen and
progesterone, and culminates with estrogen and progesterone
withdrawal.
✓ Progesterone stops endometrial growth and stimulates
endometrial differentiation.

29
Pathophysiology
✓ In anovulatory women, a corpus luteum is not formed, and the
ovary does not secrete progesterone.

✓ Without progesterone, there is no endometrial desquamation

or differentiation.

✓ Chronic unopposed estrogen causes endometrial proliferation.

✓ The endometrium becomes vascular and fragile, resulting in

noncyclic menstrual bleeding.

30
Pathophysiology
✓ The most common pathologic cause of anovulation is PCOS.
✓ The PCOS as a syndrome of ovarian dysfunction diagnosed
when two of the following characteristics exist:
✓ (a) Oligo-anovulation or anovulation
✓ (b) Clinical signs (hirsutism, acne) or laboratory evidence of
hyperandrogenism (total testosterone and sex hormone-binding
globulin; and polycystic ovary morphology on ultrasound).
✓ The Androgen excess and PCOS Society (AE-PCOS) defines
PCOS as hyperandrogenism, ovarian dysfunction (oligo-
anovulation or polycystic ovaries).
✓ Insulin resistance, hyperandrogenism, and changes in
gonadotropins also influence PCOS development.

31
Clinical Presentation and Diagnosis of
Anovulatory Bleeding
General
✓ Acute distress may or may not be present
Symptoms
✓ Irregular, heavy, or prolonged vaginal bleeding,
✓ Perimenopausal symptoms (hot flashes, etc)
Signs
✓ Acne, hirsutism, obesity
Laboratory Tests
✓ If suspect PCOS, consider free or total testosterone, fasting
glucose, fasting lipid panel.
✓ If suspect perimenopause, FSH.
Other Diagnostic Tests
✓ Pelvic ultrasound to evaluate for polycystic ovaries

32
Treatment
Desired Outcomes
✓ The desired outcomes of therapy are to stop acute
bleeding, prevent future episodes of noncyclic bleeding,
decrease long-term complications of anovulation (eg,
osteopenia and infertility), and improve overall quality of
life

33
Non-pharmacologic Therapy
✓ Nonpharmacologic treatment options depend on the
underlying cause. For all women with PCOS, weight loss may
be beneficial.

✓ In overweight or obese women, a 5% reduction in weight has

been associated with resumption of menses, improved
pregnancy rates, and decreased hirsutism, glucose, and lipid
levels.

✓ In women who have completed childbearing or who have

failed medical management, endometrial ablation, and
hysterectomy are surgical options.

34
Pharmacologic Therapy
✓ Estrogen is the recommended treatment for managing acute
bleeding episodes.
✓ It promotes endometrial growth and stabilization.
✓ Given as a CHC, it has averted emergency surgery in 95% of
patients.
✓ Long-term therapy with a CHC reduces the risk of
endometrial cancer compared to unopposed estrogen therapy.
✓ CHCs suppress ovarian hormones and adrenal androgen
production and indirectly increase sex hormone–binding
globulin (SHBG).
✓ For women with high androgen levels and related signs (eg,
hirsutism, acne), low-dose CHCs (35 mcg or less ethinyl
estradiol) are the treatment of choice

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Pharmacologic Therapy
Medroxyprogesterone Acetate
✓ Depot and intermittent oral medroxyprogesterone acetate
suppresses pituitary gonadotropins and circulating androgens
in women with PCOS.

✓ Furthermore, cyclic progesterone may benefit women older

than 40 years with anovulatory bleeding.

✓ Similar to the use of CHCs, oral medroxyprogesterone acetate

has averted emergency surgeries in 100% of patients with
acute uterine bleeding.

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Pharmacologic Therapy
Estrogen Modulators
✓ If the goal is to induce ovulation, the treatment of choice is
clomiphene citrate.
✓ It is approximately three times more effective than metformin
at achieving live births.
✓ Limited data have shown that adding metformin to clomiphene
citrate may be more effective in increasing pregnancy rates,
specially in obese women with PCOS who are resistant to
clomiphene citrate monotherapy.
✓ Treatment with clomiphene citrate is commonly
recommended following withdrawal bleeding induction with
oral medroxyprogesterone acetate, 10 mg/day for 10 days.

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Pharmacologic Therapy
Insulin-sensitizing Agents
✓ Metformin improves insulin sensitivity and is recommended in
women who cannot tolerate CHC and have IGT or type-2
diabetes mellitus.

✓ These improvements are attributed to the SHBG increase that

occurs via increased insulin sensitivity.

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Anovulatory Bleeding in Adolescents
✓ Anovulatory cycles are common in the premenarchal years.

✓ In adolescents, blood dyscrasias should be treated. Acute,

severe bleeding is managed with high-dose estrogen.

✓ Low-dose CHCs (35 mcg or less ethinyl estradiol) are the

treatment of choice in adolescents with chronic anovulation.

✓ If obesity is present, lifestyle changes are also recommended

first line, and if IGT or metabolic syndrome is present,
metformin can be recommended.

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Menorrhagia
✓ Menorrhagia describes prolonged menstrual bleeding (lasting
greater than 7 days) or cyclic, heavy menstrual bleeding (HMB;
greater than 80 mL per cycle).

✓ It is difficult to quantify menstrual blood loss in clinical

practice.

✓ Many women with less than 80 mL of blood loss seek medical

attention with concerns of flow problems.

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Epidemiology and Etiology
✓ Menorrhagia rates in healthy women range from 9% to 14%,
but can be as high as 30%.
✓ Causes of menorrhagia can be divided into systemic disorders
and reproductive tract abnormalities.
✓ Intrauterine pregnancy, ectopic pregnancy, and miscarriage are
at the top of the differential diagnosis list for any woman
presenting with heavy menses.
✓ Genital tract malignancies and infections may present with
abnormal bleeding.
✓ Systemic disorders include coagulation dysfunction such as von
Willebrand disease and platelet function disorders.
✓ Hypothyroidism is also associated with heavy menses.
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Pathophysiology
✓ Due to von Willebrand disease will cause factor VII deficiency
causing impaired platelet adhesion and increased bleeding time.
✓ Due to idiopathic thrombocytopenic will cause decrease in
circulating platelets, can be acute or chronic
✓ Due to cirrhosis will cause decreased estrogen metabolism,
underlying coagulopathy
✓ Due to hypothyroidism will make alterations in HPO axis
✓ Due to fibroids will make alterations of endometrium, changes in
uterine contractility
✓ Due to endometrial polyps will lead to alteration of endometrium
✓ Due to gynecologic cancers will lead alterations of endometrium,
uterus, cervix

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Clinical Presentation and Diagnosis of
Menorrhagia
General
✓ Acute distress may or may not be present
Symptoms
✓ Reports of heavy/prolonged menstrual flow.
✓ Fatigue and light-headedness in the case of severe blood loss.
✓ Dysmenorrhea may be an accompanying symptom
Signs
✓ Orthostatic hypotension, tachycardia, and pallor may be noted,
especially with significant acute blood loss.
Laboratory Tests
✓ Complete blood count (CBC) and ferritin levels; hemoglobin and
hematocrit results may be low.
✓ Test may be done to identify coagulation disorder(s) as a cause.

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Clinical Presentation and Diagnosis of
Menorrhagia
Other Diagnostic Tests
✓ Pelvic ultrasound
✓ Pelvic magnetic resonance imaging (MRI)
✓ Pap smear
✓ Endometrial biopsy
✓ Hysteroscopy
✓ Sonohysterogram

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Treatment

Desired Outcomes
✓ Goals of therapy are to reduce menstrual blood flow,
reduce risk of anemia, improve quality of life, and defer
the need for surgical intervention

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Treatment
Nonpharmacologic Therapy
✓ Surgical interventions are reserved for patients nonresponsive
to pharmacologic treatment and include endometrial ablation
and hysterectomy
Pharmacologic Therapy
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
✓ NSAIDs are first-line treatments for menorrhagia associated
with ovulatory cycles.
✓ They are taken only during menses, and a 20% to 35%
reduction in blood loss is reported in 75% of treated women.
✓ This reduction is directly proportional to the amount of
pretreatment blood loss. They may also improve
dysmennorhea.
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Pharmacologic Therapy
Combination Hormonal Contraceptives
✓ CHCs are beneficial to women with menorrhagia who do not desire
pregnancy.
✓ A 40% to 50% reduction in menstrual blood loss is reported in 68%
of menorrhagia patients treated with oral CHCs containing greater
than or equal to 35 mcg estradiol.
Progestins
✓ Menorrhagia may also be treated with the levonorgestrel-releasing
IUD, which consistently reduces menstrual flow by 75% to 95%, and
after 12 months, 20% to 80% of women experience amenorrhea.
✓ When compared with endometrial ablation, the levonorgestrel IUD
causes similar reductions in menstrual blood loss after 6, 12, and 24
months.
✓ Compared with hysterectomy, it leads to similar rates of satisfaction
and improved quality of life

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Pharmacologic Therapy
Tranexamic Acid
✓ Tranexamic acid reduces plasmin activity and tissue
plasminogen activator.
✓ It can be recommended for women with von Willebrand
disease.
Menorrhagia in Adolescents
✓ Up to 50% of adolescents with menorrhagia have been shown
to have a bleeding disorder, most commonly von Willebrand
disease or platelet dysfunction.
✓ Von Willebrand disease is estimated that 5% to 36% of
adolescents presenting with heavy menses have this disorder.
✓ Platelet function disorders exist in 2% to 44% of adolescents
with menorrhagia.
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Case Study
✓ A 22-year-old white woman presents to her physician
reporting severe pelvic pain and cramping during menses that
results in 1 to 2 missed work days each menstrual cycle. Her
last menstrual cycle was 9 days ago, and she had her first
menstrual cycle at age 11. She is sexually active with one
partner and has had 5 sexual partners in the past. She has a
history or Chlamydia in the past. She has been using
acetaminophen or ibuprofen as needed for pain and is a
current smoker. She does not follow a diet or exercise
regimen.
✓ What risk factors does this patient have for primary
dysmenorrhea?
✓ What risk factors does the patient have for secondary
dysmenorrhea?

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Case Study
✓ PMH: asthma
✓ PSH: none
✓ FH: Mother and father are alive and well. She has two younger
siblings (ages 17 and 12) who are alive and well.
✓ SH: (+) smoking; (–) drug use; (+) alcohol use (2–4 drinks per
week)
✓ Meds: Fluticasone 110 mcg 2 puffs twice daily and albuterol 90
mcg 2 puffs prn SOB
✓ Past Gynecologic Hx: Menarche at age 11; never pregnant;
✓ (+) sexual activity; 6 sexual partners; (+) history of Chlamydia;
✓ (+) history of painful menses beginning at age 12; (+) heavy
menstrual flow; menstrual cycle 26 to 28 days.
✓ ROS: (–) fatigue; (–) headaches; (+) mild acne on face and chest;
(+) moderate to severe pelvic pain with menses

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Case Study
✓ General: Thin-appearing white woman, in no acute distress
✓ VS: BP 116/64, P 74, RR 14, Wt 128 lbs (58.2 kg), Ht 5’4” (163
cm), BMI: 22 kg/m2
✓ HEENT: (–) hirsutism
✓ Breasts: (–) galactorrhea
✓ Pelvic examination: normal appearance of external genitalia
and vagina, cervix without lesions, uterus mid-position without
masses.
✓ Labs: (–)hCG
✓ What is your assessment of this patient’s condition?
✓ What nonpharmacologic and pharmacologic therapies are
recommended for this patient?

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Case Study
✓ A 40-year-old woman presents to your office for a routine
gynecologic examination. She entered menarche at the age of
12. Her last menstrual period was 3 months ago. Her periods
are often irregular and occur about every 2 to 3 months. All
previous Pap smears have been normal, and there is no history
of sexually transmitted infections. She has had one sexual
partner whom she is married to. She had one successful
pregnancy that took “several years” and three courses of
clomiphene due to “follicles” on her ovaries. Her PMH is
significant for diabetes and hypertension for which she takes
metformin 1000 mg by mouth twice daily and lisinopril 10 mg
by mouth once daily. She is married and is not using any form
of contraception. She notes that they have decided not to
continue to try to have children. On examination, she is an
overweight female with mild hirsutism.

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Case Study
✓ Labs: Urine HCG negative, free testosterone 100 ng/dL (3.47
nmol/L) (elevated), TSH 2.1 μIU/mL (2.1 mIU/L) (within normal
limits), prolactin 9 ng/mL (9 mcg/L [391 pmol/L]) (within
normal limits), fasting glucose 120 mg/dL (6.7 mmol/L). Fasting
lipid panel: total cholesterol 181 mg/dL (4.68 mmol/L), HDL
cholesterol 58 mg/dL (1.50 mmol/L), triglycerides 65 mg/dL
(0.73 mmol/L), LDL cholesterol 110 mg/dL (2.84 mmol/L)
✓ Pelvic ultrasound: 17 follicles in right ovary, 13 follicles in left
ovary, increased ovarian volume of 12 mL
1. What anovulatory disorder is most likely present?
2. What signs/symptoms support this conclusion?
3. What pharmacologic therapies are recommended for this
patient?

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Case Study
✓ A 14-year-old girl presents to her physician reporting
moderate pelvic pain and cramping during menses. She also
notes that her menses are “heavy” and require a change in
tampon every 3–4 hours. Her last menstrual cycle was 12 days
ago, and she had her first menstrual cycle at age 12. She is not
sexually active. She does not take any routine medications. She
is on the high school volleyball team.
✓ Identify the treatment goals for this patient’s menorrhagia.
✓ What diagnostic tests should be considered?
✓ What pharmacologic therapies are recommended for this
patient?
✓ What monitoring parameters are recommended to assess
efficacy and safety of the therapeutic options?

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Reference
✓ Pharmacotherapy-By Joseph T.Diprio,9th edition.
✓ Pharmacotherapy A Pathophysiologic Approach-by
Joseph-T.Diprio 9th Edition.
✓ Pharmacotherapy Principles & Practice 4th edition
Marie A. Chisholm, Joseph-T. Diprio

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