t4

.
Chapter 000

WOMEN'S HEALTH
 • LEARNING
ndrome,OBJECTIVES.
dysmenorrhea and premenstrual
syndrome.
Aft
er  Understand and explain etiopathogenesis of polycystic ovary syndrome, dysmenorrhea
and premenstrual syndrome.
stu
dyi  Understand clinical manifestations of polycystic ovary syndrome, dysmenorrhea and
ng premenstrual syndrome.
the
 Understand diagnostic parameters of polycystic ovary syndrome, dysmenorrhea and
ch
premenstrual syndrome.
apt
er,  Explain non-pharmacological and pharmacological management of polycystic ovary
syndrome, dysmenorrhea and premenstrual syndrome.
stu
de  Assess their knowledge and understanding of the chapter through practice questions.
nts
will
be a POLYCYSTIC OVARY SYNDROME
abl
14.1.1 Introduction to Polycystic Ovary Syndrome
e
to: Polycystic ovarian syndrome (PCOS) is an endocrinopathy in women of reproductive age
U and is characterized by menstrual disorders (such as oligomenorrhea, amenorrhea,
n menorrhagia, infertility), hyperandrogenism (which primarily manifests as hirsutism, acne,
d and, occasionally, virilization), obesity, and presence of polycystic ovaries. It is thought to be
e due to reduced peripheral insulin sensitivity, causing excess androgen production.
r
s  Oligomenorrhea is infrequent menstrual periods.
t  Amenorrhea is the absence of monthly menstrual periods.
a
n  Menorrhagia is menstrual bleeding that lasts> 7 days.
d
 Hirsutism is abnormal growth of hair on a woman's face and body.
b  Virilization is the development of male physical characteristics.
a
14.1'102 Etiopathogenesis of Polycystic Ovary Syndrome
s
i 1. Peripheral insulin resistance leading to hyperinsulinemia. This is the major trigger for
c disordered ovarian function and androgen excess. Hyperinsulinemia may manifest
s clinically as part of a metabolic syndrome that includes diabetes mellitus (OM),
o dyslipidemia, and coronary artery disease (CAD).
f
p (14.1 )
o
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Pharmacotherapeutics (S.Y.D.Pharm.) 14.2 Women's Health

2. Decreased sex hormone-binding globulin (SHBG) causes an increase in levels of free

active androgens (hyperandrogenism) which accounts for the more marked hirsutism,
acne and other manifestations of hyperandrogenism.
3. Elevated estrone stimulates hyperplasia of ovarian stroma theca cells, and the
unopposed
estrogen effects on the endometrium may lead to abnormal uterine bleeding and
increased risk of endometrial cancer.
4. Biochemical profile of peos may include
 Increased androgen levels
 Increased serum concentrations of luteinizing hormone (LH)
 Increased testosterone and androstenedione
 Increased prolactin
 Increased insulin
 Low to normal follicle-stimulating hormone (FSH)
 Low to normal estradiol while estrone level is increased
 Decreased sex hormone binding-globulin (SHBG)
Risk Factors:
 Age (reproductive age)
 Presence of other conditions such as obesity, subclinical vascular disease, type 2
diabetes mellitus, dyslipidemia, non-alcoholic steatohepatitis and obstructive sleep
apnea.
 Genetics
 Ethnicity or race
14.1.3 Clinical Manifestations of Polycystic Ovary Syndrome
Onset of symptoms typically occurs during adolescence.
1. Menstrual irregularities: Oligomenorrhea, amenorrhea, menorrhagia, infertility or
difficulties conceiving.

2. Insulin resistance and associated conditions: Obesity, increased risk of sleep

apnea, nonalcoholic fatty liver disease.

3. Skin conditions: Hirsutism, androgenic alopecia, acne vulgaris, oily skin and
acanthosis nigricans

4. Psychiatric conditions: Depression and anxiety disorders

14.1.4 Diagnosis and Investigation of Polycystic Ovary Syndrome

Use the Rotterdam criteria to establish the clinical diagnosis.
Rotterdam criteria are a set of diagnostic criteria for polycystic ovarian syndrome.
Diagnosis requires at least two of the following: oligoovulation and/or anovulation, evidence
of hyperandrongenism (e.g., acne, hirsutism, male-pattern hair loss), and polycystic ovaries
on ultrasonography. -
2.

Pharmacotherapeutics (S.Y.D.Pharm.) 14.3 Women's Health

14.1.5 Management of POlycystic Ovary Syndrome

Management of polycystic ovary syndrome consists of lifestyle modifications combined
with pharmacotherapy, which is tailored to the patient's reproductive goals. In women who
do not wish to get pregnant, combined oral contraceptives (CaCs) pills are indicated to
control menstrual irregularities and treat hyperandrogenism. For women who wish to get
pregnant, the goal of treatment is to induce ovulation (e.g., with letrozole).

All patients should be screened for comorbidities and risk factors and receives specific
treatment for these when necessary.

14.1.5.1-Non Pharmacological Management of Polycystic Ovary

Syndrome

In all pcas patients:

Lifestyle Modification:
1. There is no particular diet plan that is recommended for pcas. Modify diet so as to
maintain euglycemia and promote weight loss in an obese patient. Target BMI < 25
kg/m2

2. Exercise and weight reduction can help reverse the metabolic problems in pcas by
improving ovarian function and the associated hormonal aberrations.

3. Exercise and weight reduction decrease risk of diabetes and cardiovascular disease
(CVD).

4. Improvement in physical fitness and reduction in body fat help in resumption of

ovulation and increase in fertility especially in anovulatory obese women with pcas.

5. Weight reduction helps lower circulating androgen, decreases hirsutism, leads to

spontaneous resumption of menses, improves insulin resistance in obese patients
and glucose and lipid levels.

6. pcas patients should be informed of and screened for risk factors of CVD, anxiety
and depressive symptoms to ensure adherence to lifestyle changes.
7. Stop cigarette smoking.
Additional fertility interventions:

 Laparoscopic ovarian drilling

 In vitro fertilization
Management of Hirsutism:
Non-pharmacological therapy is first-line to treat hirsutism. Moderate and localized
hirsutism may be treated with hair removal by shaving, plucking, waxing, laser therapy,
electrolysis, depilatory creams or photoepilation.

14.1.5.2 Pharmacological Management of Polycystic Ovary Syndrome

Goals of pharmacotherapy of polycystic ovary syndrome include:
1. Reducing risk factors for type 2 diabetes mellitus and CVD.
2. Managing underlying metabolic abnormalities.
Pharmacotherapeutics (S.Y.D.Pharm.) 14.4 Women's Heal

3. Treating hyperandrogenic features.

4. Preventing endometrial hyperplasia and carcinoma.
5. Inducing ovulation in women who wish to become pregnant and providing
contraception for those who do not wish to become pregnant.
6. Combined Oral Contraceptives (COCs):
Indication: first-line treatment for hyperandrogenism and/or menstrual cycle
abnormalities in pcas patients who do not desire pregnancy.

Low-dose progestins with minimal androgenic potential (e.g., norgestimate, desogestrel,

gestodene, drospirenone, dienogest and ethynodiol diacetate) + estrogen preparation
(ethinyl estradiol or equivalent) are preferred for long-term management.

cacs may take a minimum of 6 months to notice a benefit in hirsutism and acne. It helps
reduce the risk of endometrial hyperplasia and carcinoma by antagonizing estrogen's
proliferative effect on the endometrium. It inhibits gonadotropin stimulation of the ovary
resulting in reduced androgen production. It causes lowering of LH levels without surges and
the estrogen component stimulates SHBG production by the liver. SHBG lowers free
androgen.

Many combination oral contraceptives are available.

Table 14.1: Combined oral contraceptive preparations

PROGESTIN ESTROGEN
1. Norgestrel 0.3 mg Ethi nylestrad iol 3Oll9
2. Norgestrel 0.5 mg Ethinylestradiol 5Oll9
3. Levonorgestrel 0.25 mg Ethinylestradiol 5Oll9
4. Levonorgestrel 0.15 mg Ethinylestradiol 3Oll9
5. Levonorgestrel 0.1 mg Ethinylestradiol 2Oll9
6. Desogestrel 0.15 mg Ethinylestradiol 3Oll9
2. Antiandrogen Agents:

e.g., Cyproterone, spironolactone, finasteride, flutamide

Indications: can be considered for treatment of androgen-related alopecia, acne and
hirsutism in patients unable to take or tolerate cacs.

Cyproterone when combined with an estrogen . provides control of menses and

contraception.

These drugs are teratogenic and pose a risk of feminization of the external genitalia in a
male fetus, thus effective contraception must be utilized.

3. Management for Amenorrhea:

Medroxyprogesterone acetate: It is a synthetic progestogen that inhibits ovulation
resulting in endometrial thinning. It is used to induce withdrawal bleeding in pcas women
•
Pharmacotherapeutics (S.Y.D.Pharm.) 14.5 Women's Health

who have irregular menstrual cycle. It may be given for patients who cannot take estrogen-
containing pills or those who do not wish to take oral contraceptives (OCs). It does not
provide birth control.
4. Eflornithine:
It inhibits growth of facial hair. Its onset of action may take 4-8 weeks for facial hirsutism.
Its postulated mechanism of action includes irreversible inhibition of ornithine decarboxylase
activity in the skin resulting in reduced rate of hair growth.

5. Spironolactone and Finasteride:

These agents are antiandrogen effective in treating hirsutism and acne but should only
be considered in women who do not desire pregnancy.

Spironolactone is a mineralocorticoid antagonist with a structure similar to testosterone,

it competes with androgen by binding to receptors.

Finasteride is a S-a reductase inhibitor which acts by inhibiting the conversion of

testosterone to dihydrotestosterone and by blocking androgen receptor.

6. Management for Metabolic Risks (Insulin Resistance and Glucose Intolerance):

Metformin:
It is the second-line treatment for menstrual irregularity in patients unable to take or
tolerate COCs. It may be added to COCs and lifestyle modification to improve metabolic
outcomes. It significantly improves insulin concentration, insulin sensitivity and serum
androgen concentration along with a reduction in LH and an increase in SHBG concentration.

In hyperinsulinemic PCOS, metformin is used to restore menstrual cyclicity and induce

ovulation with and without the addition of Clomifene.

7. Patients Planning to Become Pregnant:

The goals of treatment for patients who wish to become pregnant are induction of
ovulation and management of comorbidities. The first-line therapy for ovulation induction is
letrozole. Its mechanism of action is aromatase inhibition that reduces estrogen production,
stimulating FSH secretion and inducing ovulation.

Clomiphene is an alternative to letrozole.

Low-dose regimen of the exogenous gonadotropins (exogenous FSH and human
menopausal gonadotropin) are the second-line treatment for ovulation induction.

a DYSMENORRHEA
14.2.1 Introduction to Dysmenorrhea

Dysmenorrhea is a symptom of pain shortly before or during menstruation. It is further

divided into primary dysmenorrhea and secondary dysmenorrhea.

Primary dysmenorrhea is a recurrent lower abdominal pain shortly before or duri g

menstruation without demonstrable pelvic pathology.
Pharmacotherapeutics (S.Y.D.Pharm.) 14.6 Women's Health

Secondary dysmenorrhea is a recurrent lower abdominal pain shortly before or during

menstruation caused by an underlying pelvic pathology.
14.2.2 Etiopathogenesis of Dysmenorrhea
(I) Primary dysmenorrhea:
Etiology:
 The etiology of primary dysmenorrhea is yet to be understood completely. It is
associated with some risk factors such as early menarche, nulliparity, stress, smoking,
obesity, positive family history.

 Menarche is the start of menstruation.

 Nulliparity is a condition or state in which a woman has never given birth to a live
child.

Pathophysiology:
 Symptoms of primary dysmenorrhea are caused by endometrial prostaglandins
PGF2a and PGE2 that are released from the endometrium at the time of
menstruation. These prostaglandins cause vasoconstriction/ischemia and stronger,
sustained uterine contractions.

(D) Secondary dysmenorrhea:

Etiology:
(a) Uterine causes:
 Pelvic inflammatory disease (PID)
 Intrauterine device (IUD)

 Adenomyosis (It is a condition in which endometrial tissue exists within and grows
into the myometrium of the uterus).
 Fibroids (also called as leiomyomas are non-cancerous muscular tumors that grow in

the wall of the uterus).

 Cervical polyps (These are small, elongated benign tumors that grow on the cervix.

They typically cause vaginal bleeding).

(b) Extrauterine causes:
 Endometriosis (It is a chronic, benign condition in which endometrial tissue is found
outside the uterus, commonly in the fallopian tubes, ovaries, bladder).
 Adhesions
 Functional ovarian cysts

 Inflammatory bowel disease

14.2.3 Clinical Manifestations of Dysmenorrhea

Primary Dysmenorrhea:
Symptoms of primary dysmenorrhoea usually occur during the first 1-3 days of
menstruation. Symptoms include intermittent painful spasms, crampy pain in the lower
Pharmacotherapeutics (S.Y.D.Pharm.) 14.7 Women's Health

abdomen and the suprapubic area which may radiate to the back or thighs. The pain may
also be described as a dull ache or as a stabbing pain.
Headaches, nausea and vomiting, diarrhea, light headed ness, fatigue, fever, muscle
cramps, nervousness, fainting and poor sleep quality are common accompanying symptoms.
Secondary Dysmenorrhea:

In general, symptoms depend on the underlying cause.

1. Pelvic pain occurring at times other than menses.
2. When dysmenorrhea occurs during the first 1-2 cycles after menarche consider
congenital outflow tract obstruction.

3. When dysmenorrhea occurs after the age of 20 years or late onset of dysmenorrhea
after a history of previous menstrual cycles without pain consider ectopic or
threatened spontaneous abortion.

4. When heavy menstrual flow or irregular cycles occur consider adenomyosis, fibroids,
and polyps.
5. If urinary, musculoskeletal or gastrointestinal (GI) symptoms are there consider non-
gynecologic process.

6. Signs of secondary dysmenorrhea caused by endometriosis are progressive

dysmenorrhea, family history of endometriosis, dyspareunia, postcoital bleeding and
Infertility.

7. Partial or no response to therapy with NSAIDs, oral contraceptives (O(s), or both.

14.2.4 Diagnosis and Investigation of Dysmenorrhea

Diagnosis of primary dysmenorrhea is based on clinical presentation, history and physical

exam. Diagnosis of secondary dysmenorrhea depends on the underlying cause and pelvic
ultrasonography, magnetic resonance imaging (MRI) and diagnostic laparoscopy may be
considered.

14.2.5 Management of Dysmenorrhea

14.2.5.1 Non-Pharmacological Management of Dysmenorrhea
Motivate patient to adopt healthy lifestyle changes such as stop smoking, exercise
regularly, adopt a low-fat vegetarian diet, do relaxation techniques (yoga). These
modifications may decrease painful periods.

Topical Heat Therapy:

Topical application of heat to the lower abdomen with hot compress, heated pad, or hot
water bottle offers some relief.

Surgical Intervention:
(i) Laparoscopic Uterine Nerve Ablation: It is done either by cautery or (02 lase .•
indicated for patients with severe
refractory dysmenorrhea.
Pharmacotherapeutics (5. Y .D.Pharm.) 14.8 Women's Health

(ii) Laparoscopic Presacral Neurectomy: It may be used in women, who desire fertility (i
preservation, as an additional procedure to the laparoscopic treatment of v
endometriosis for dysmenorrhea.
)
(iii) Endometrial Ablation: It may decrease dysmenorrhea with menorrhagia in women
C
who do not desire fertility preservation.
o
(iv) Hysterectomy: It is the surgical removal of all or part of the m
uterus. b
14.2.5.2 Pharmacological Management of i
Dysmenorrhea n
Primary Dysmenorrhea: e
d
1. Symptomatic treatment: Pain relief with NSAIDs:
E
NSAID is the first line treatment in most women with primary dysmenorrhea. It is most
t
effective when started 1-2 days before the onset of menses and continued for the usual
duration of cramps. NSAIDs inhibit the production and release of prostaglandin. GI related h
side effects of NSAIDs are reduced when taken with or after food or milk. Pharmacologic i
properties and the severity of side effects determine the choice and dosage of NSAIDs. n
Treatment may start with a propionic acid derivative (e.g., Ibuprofen) then switch to a y
fenamate (e.g., Mefenamic acid) if pain relief is inadequate. Aspirin is usually not used l
because of its lack of anti-inflammatory action at usual doses. It may also increase
e
menstrual
s
flow. COX-2 selective NSAIDs may cause fewer GI side effects when compared to non
selective NSAIDs. t
r
Contraindications to NSAIDs: Peptic ulceration and hypersensitivity to NSAID. a
2. Oral Contraceptives (OCs): d
It is the first line therapy for patients who also desire contraception. OCs suppresses i
endometrial prostaglandin production by inhibiting ovulation and by preventing normal o
synchronous endometrial growth and differentiation. They decrease menstrual flow and
l
uterine contractions thus reducing dysmenorrhea. OCs may take upto 3 cycles of
a
treatment
for menstrual pain to diminish noticeably. n
d
Contra indications to OCs include current pregnancy, breast carcinoma, endometrial
N
cancer history of venous or arterial thrombosis, cardiovascular disease (CVD), hepatic
o
dysfunction, systemic lupus erythematosus (SLE), cerebrovascular disease, cholestatic
r
jaundice, undiagnosed vaginal bleeding, and breastfeeding.
e
Various oral contraceptives are available (See Table 14.1). l
3. Other Hormonal Contraception: g
(i) Levonorgestrel-releasing intrauterine e
system s
(ii) Depot Medroxyprogesterone acetate t
(iii) Etonogestrel subdermal implant r
omin vaginal ring
Pharmacotherapeutics (S.Y.D.Pharm.) 14.9 Women's Health

4. Combination of NSAIDs and OCs:

Combination therapy consisting of NSAIDs and OCs may be useful in refractory cases.
NSAIDs and OCs work via different mechanisms of actions.
Secondary Dysmenorrhea:
Treatment of secondary dysmenorrhea depends on the underlying cause.

 PREMENSTRUAL SYNDROME
14.3.1 Introduction to Premenstrual Syndrome

Premenstrual syndrome (PMS) is a recurrent luteal-phase disorder characterized by mild

to moderate psychiatric, gastrointestinal, and/or neurological symptoms, occurring during
the 7 to 10 days before menses and usually goes away 1 to 2 days after the menstrual period
starts.

14.3.2 Etiopathogenesis of Premenstrual Syndrome

The etiology and pathophysiology of premenstrual syndrome is unclear. PMS is linked to
the luteal phase. It is proposed that hormonal fluctuations of the menstrual cycle, hormonal
disproportion like estrogen surplus and progesterone deficiency and serotonin deficiency
may be involved in the etiopathogenesis of PMS.

14.3.3 Clinical Manifestations of Premenstrual Syndrome

Onset of symptoms occur 7 to 10 days before menstruation.
 Psychiatric symptoms are mood swings, irritability, confusion, social withdrawal,
drowsiness, exhaustion, lethargy, depression, anxiety, and aggressiveness.

 Pain related symptoms are headache, backache, abdominal pain, bodyache,

dyspareunia, breast tenderness.

 Gastrointestinal changes are bloating, nausea, diarrhea, and changes in appetite

(food cravings).

 Neurological symptoms are migraine, poor concentration, and increased sensitivity to

stimuli.

 Weight gain

 Tendency to edema formation

14.3.4 Diagnosis and Investigation of Premenstrual Syndrome

Diagnosis is based on symptoms alone (maintaining a PMS diary).
Concomitant medical or psychiatric disorders should be ruled out.
14.3.5 Management of Premenstrual Syndrome
The main goal of PMS treatment is symptom relief and to reduce its effects on routine
activities. Treatment is symptomatic. Treatments available are non-pharmacological therapy
mainly lifestyle modifications and cognitive and behavioral therapies (CBT) and combination
of pharmacotherapies (such as NSAIDs, oral contraceptive pills, SSRls, anxiolytic agents) with
non-pharmacological treatments.
3.

Women's
Pharmacotherapeutics 14. Health
(S.Y.D.Pharm.) 10

14.3.5.1 Non-Pharmacological Management of Premenstrual Syndrome

1. Lifestyle modification 2. Cognitive-behavioral therapy (CBT):
Life-style advice should be offered to all women as first line of treatment of PMS.
 Daily charting of symptoms for two to three months (maintaining a PMS diary).
 Adequate rest and sleep
 Stress management (yoga/meditation)
 Dietary changes like increase complex carbohydrate meals, reduce or eliminate salt,
and eat several small meals per day.
 Avoid individual triggers like alcohol, caffeine, or nicotine
 Regular exercise like brisk walk 1-2 miles per day for 4-5 days/week. This may help
alleviate bloating as well as irritability, anxiety, and insomnia.
Cognitive-behavioral therapy (CBT) (Describe previously)
14.3.5.2 Pharmacological Management of Premenstrual Syndrome
First-line treatment include NSAIDs (e.g., naproxen), oral contraceptive pills (OCPs), SSRIs
(e.g., fluoxetine) in the case of severe PMS.
Dietary supplements: Reduce symptoms and improve mood swings
Calcium (1,200 rnq/day)
Vitamin D
Vitamin E
In the case of water retention/bloating: Diuretics (e.g., spironolactone), magnesium
EXERCISE
1. What is polycystic ovary syndrome?

2. Explain etiopathogenesis of polycystic ovarian syndrome.

3. Mention risk factors of polycystic ovarian syndrome.
4. Explain clinical manifestations of polycystic ovarian syndrome.
5. Write a note on:
(a) Management of polycystic ovary syndrome
(b) Non-pharmacological management of polycystic ovary syndrome
(c) Pharmacological management of polycystic ovary syndrome
(d) Combined oral contraceptives (COCs)
6. Write goals of pharmacotherapy of polycystic ovary syndrome.
7. What is dysmenorrhea?
8. Explain etiopathogenesis of
(a) primary dysmenorrheal,
(b) etiology of secondary dysmenorrhea
9. Explain clinical manifestations of
(a) primary dysmenorrhea,
(b) secondary dysmenorrhea