2. Menstruation
Menstruation is the shedding of the lining of the
uterus (endometrium) accompanied by bleeding. It
occurs in approximately monthly cycles throughout a
woman's reproductive life, except during pregnancy.
Menstruation starts during puberty (at menarche) and
stops permanently at menopause.
3. Menstrual Cycle
By definition, the menstrual cycle begins with the first
day of bleeding, which is counted as day 1. The cycle
ends just before the next menstrual period. Menstrual
cycles normally range from about 25 to 36 days. Only
10 to 15% of women have cycles that are exactly 28
days. Also, in at least 20% of women, cycles are
irregular. That is, they are longer or shorter than the
normal range. Usually, the cycles vary the most and
the intervals between periods are longest in the years
immediately after menarche and before menopause.
4. Menstrual Bleeding
Menstrual bleeding lasts 3 to 7 days, averaging 5 days.
Blood loss during a cycle usually ranges from 1/2 to 2
1/2 ounces. A sanitary pad or tampon, depending on
the type, can hold up to an ounce of blood. Menstrual
blood, unlike blood resulting from an injury, usually
does not clot unless the bleeding is very heavy.
5. Pathophysiology: Menstruation
Complex interactions among hormones control the start of menstruation during
puberty, the rhythms and duration of menstrual cycles during the reproductive years,
and the end of menstruation at menopause (which is usually defined as beginning 12
months after a woman's last period). The interactions occur in the following sequence:
Hormonal control of menstruation begins in the hypothalamus (the part of the brain that
coordinates and controls hormonal activity).
The hypothalamus releases gonadotropin-releasing hormone in pulses.
Gonadotropin-releasing hormone stimulates the pituitary gland to produce two hormones
called gonadotropins: luteinizing hormone and follicle-stimulating hormone.
Luteinizing hormone and follicle-stimulating hormone stimulate the ovaries.
The ovaries produce the female hormones estrogen and progesterone , which ultimately
control menstruation.
Estrogen and progesterone stimulate the uterus and breasts to prepare for possible
fertilization.
The menstrual cycle has three phases: follicular (before release of the egg), ovulatory
(egg release), and luteal (after egg release).
Hormones produced by other glands, such as the adrenal glands and the thyroid gland,
can affect the functioning of the ovaries and menstruation.
7. Menstrual Disorders Defined
During the reproductive years, vaginal bleeding may
be abnormal or dysfunctional when menstrual periods
are too heavy or too light, last too long, occur too
often, or are irregular. Any vaginal bleeding that occurs
before puberty or after menopause is considered
abnormal until proven otherwise. Most causes of
abnormal vaginal bleeding are not serious.
8. Menstrual Disorders: Types
Amenorrhea: No periods
Primary Amenorrhea: No periods ever starting (at puberty)
Secondary Amenorrhea: Periods that have stopped
Dysmenorrhea: Menstrual cramps or painful periods
Hypomenorrhea: Unusually light periods
Menometrorrhagia: Heavy bleeding during menstrual periods and bleeding that occurs frequently and irregularly
between periods
Menorrhagia (Hypermenorrhea): Unusually long and/or heavy periods
Metrorrhagia: Bleeding that occurs frequently and irregularly between periods
Oligomenorrhea: Unusually infrequent periods
Polymenorrhea: Unusually frequent periods
Postmenopausal Bleeding: Bleeding that occurs after menopause
Premenstrual Dysphoric Disorder: Severe psychologic symptoms that occur before the start of a period, end when or
shortly after the period starts, and interfere with daily activities and/or relationships
Premenstrual Syndrome (PMS): Physical and psychologic symptoms that occur before the start of a period
NOTE: Some disorders that are related to the reproductive organs but not specifically to the menstrual cycle, such as
pelvic congestion syndrome and polycystic ovary syndrome, cause some of the same symptoms as menstrual disorders.
9. Pathophysiology: Amenorrhea
Primary amenorrhea is failure of menses to occur by one of the
following:
Age 16 or 2 yr after the onset of puberty
About age 14 in girls who have not gone through puberty (eg,
growth spurt, development of secondary sexual characteristics)
If patients have had no menstrual periods by age 13 and have no
signs of puberty (eg, any type of breast development), they should
be evaluated for primary amenorrhea.
Secondary amenorrhea is cessation of menses after they have
begun. Usually, patients should be evaluated for secondary
amenorrhea if menses have been absent for ≥ 3 mo or ≥ 3 typical
cycles because from menarche until perimenopause, a menstrual
cycle lasting > 90 days is unusual.
10. Evidence-Based Research
Normally, the hypothalamus generates pulses of gonadotropin-releasing hormone (GnRH). GnRH
stimulates the pituitary to produce gonadotropins (follicle-stimulating hormone [FSH] and
luteinizing hormone [LH]—see Female Reproductive Endocrinology : Menstrual Cycle), which are
released into the bloodstream. Gonadotropins stimulate the ovaries to
produce estrogen (mainlyestradiol ), androgens (mainly testosterone ), and progesterone. These
hormones do the following:
FSH stimulates tissues around the developing oocytes to convert testosterone to estradiol .
Estrogen stimulates the endometrium, causing it to proliferate.
LH , when it surges during the menstrual cycle, promotes maturation of the dominant oocyte, release
of the oocyte, and formation of the corpus luteum, which produces progesterone.
Progesterone changes the endometrium into a secretory structure and prepares it for egg
implantation (endometrial decidualization).
If pregnancy does not occur, estrogen and progesterone production decreases, and the endometrium
breaks down and is sloughed during menses. Menstruation occurs 14 days after ovulation in typical
cycles.
When part of this system malfunctions, ovulatory dysfunction occurs; the cycle of gonadotropin-
stimulated estrogen production and cyclic endometrial changes is disrupted, resulting in anovulatory
amenorrhea, and menstrual flow may not occur. Most amenorrhea, particularly secondary
amenorrhea, is anovulatory.
However, amenorrhea can occur when ovulation is normal, as occurs when genital anatomic
abnormalities (eg, congenital anomalies causing outflow obstruction, intrauterine adhesions
[Asherman syndrome]) prevent normal menstrual flow despite normal hormonal stimulation.
11. Amenorrhea is usually classified as
Anovulatory (see Table: Some Causes of Anovulatory Amenorrhea)
Ovulatory (see Table: Some Causes of Ovulatory Amenorrhea)
Each type has many causes, but overall, the most common causes of amenorrhea include
Pregnancy (the most common cause in women of reproductive age)
Constitutional delay of puberty
Functional hypothalamic anovulation (eg, due to excessive exercise, eating disorders, or
stress)
Use or abuse of drugs (eg, oral contraceptives, depoprogesterone, antidepressants,
antipsychotics)
Breastfeeding
Polycystic ovary syndrome
Contraceptives can cause the endometrium to thin, sometimes resulting in amenorrhea;
menses usually begin again about 3 mo after stopping oral contraceptives.
Antidepressants and antipsychotics can elevate prolactin, which stimulates the breasts to
produce milk and can cause amenorrhea.
Some disorders can cause ovulatory or anovulatory amenorrhea. Congenital anatomic
abnormalities cause only primary amenorrhea. All disorders that cause secondary
amenorrhea can cause primary amenorrhea.
12. Anovulatory amenorrhea
The most common causes (see Table: Some Causes of Anovulatory
Amenorrhea) involve a disruption of the hypothalamic-pituitary-
ovarian axis. Thus, causes include
Hypothalamic dysfunction (particularly functional hypothalamic
anovulation)
Pituitary dysfunction
Primary ovarian insufficiency (premature ovarian failure)
Endocrine disorders that cause androgen excess (particularly polycystic
ovary syndrome)
Anovulatory amenorrhea is usually secondary but may be primary if
ovulation never begins—eg, because of a genetic disorder. If ovulation
never begins, puberty and development of secondary sexual
characteristics are abnormal. Genetic disorders that confer a Y
chromosome increase the risk of ovarian germ cell cancer.
13. Ovulatory amenorrhea
The most common causes (see Table: Some Causes of Ovulatory
Amenorrhea) include
Chromosomal abnormalities
Congenital anatomic genital abnormalities that obstruct menstrual flow
Obstructive abnormalities are usually accompanied by normal hormonal
function. Such obstruction may result in hematocolpos (accumulation of
menstrual blood in the vagina), which can cause the vagina to bulge, or in
hematometra (accumulation of blood in the uterus), which can cause uterine
distention, a mass, or bulging of the cervix. Because ovarian function is
normal, external genital organs and other secondary sexual characteristics
develop normally. Some congenital disorders (eg, those accompanied by
vaginal aplasia or a vaginal septum) also cause urinary tract and skeletal
abnormalities.
Some acquired anatomic abnormalities, such as endometrial scarring after
instrumentation for postpartum hemorrhage or infection (Asherman
syndrome), cause secondary ovulatory amenorrhea.
14. Management
Girls are evaluated if
They have no signs of puberty (eg, breast development, growth spurt) by age 13.
Pubic hair is absent at age 14.
Menarche has not occurred by age 16 or by 2 yr after the onset of puberty (development of secondary sexual characteristics).
Women of reproductive age should have a pregnancy test after missing one menses. They are evaluated for amenorrhea if
They are not pregnant and have missed menstrual cycles for ≥ 3 mo or ≥ 3 typical cycles.
They have < 9 menses a year.
They have a sudden change in menstrual pattern.
History
History of present illness includes the following:
Whether menses have ever occurred (to distinguish primary from secondary amenorrhea) and, if so, how old patients were at menarche
Whether periods have ever been regular
When the last normal menstrual period occurred
How long and heavy menses is
Whether patients have cyclic breast tenderness and mood changes
When they reached certain growth and development milestones, including age at thelarche (development of breasts at puberty)
Review of systems should cover symptoms suggesting possible causes, including the following:
Galactorrhea, headaches, and visual field defects: Pituitary disorders
Fatigue, weight gain, and cold intolerance: Hypothyroidism
Palpitations, nervousness, tremor, and heat intolerance: Hyperthyroidism
Acne, hirsutism, and deepening of the voice: Androgen excess
For patients with secondary amenorrhea, hot flushes, vaginal dryness, sleep disturbance, fragility fractures, and decreased libido:Estrogen deficiency
Patients with primary amenorrhea are asked about symptoms of puberty (eg, breast development, growth spurt, presence of axillary and pubic hair) to help determine whether ovulation has occurred.
Past medical history should note risk factors for the following:
Functional hypothalamic anovulation, such as stress; chronic illness; new drugs; and a recent change in weight, diet, or exercise intensity
In patients with secondary amenorrhea, Asherman syndrome (eg, D & C, endometrial ablation, endometritis, obstetric injury, uterine surgery)
Drug history should include specific questions about use of drugs, such as the following:
Drugs that affect dopamine (eg, antihypertensives, antipsychotics, opioids, tricyclic antidepressants)
Cancer chemotherapy drugs (eg, busulfan, chlorambucil, cyclophosphamide)
Sex hormones that can cause virilization (eg, androgens, estrogens , high-dose progestins, OTC anabolic steroids)
Contraceptives, particularly recent use
Systemic corticosteroids
OTC products and supplements, some of which contain bovine hormones or interact with other drugs
Family history should include height of family members and any cases of delayed puberty or genetic disorders in family members, including Fragile X syndrome.
Physical examination
Clinicians should note vital signs and body composition and build, including height and weight, and should calculate body mass index (BMI). Secondary sexual characteristics are evaluated; breast and
pubic hair development are staged using Tanner method. If axillary and pubic hair is present, adrenarche has occurred.
With the patient seated, clinicians should check for breast secretion by applying pressure to all sections of the breast, beginning at the base and moving toward the nipple. Galactorrhea (breast milk
secretion not temporally associated with childbirth) may be observed; it can be distinguished from other types of nipple discharge by finding fat globules in the fluid using a low-power microscope.
Pelvic examination is done to detect anatomic genital abnormalities; a bulging hymen may be caused by hematocolpos, which suggests genital outflow obstruction. Pelvic examination findings also
help determine whether estrogen has been deficient. In postpubertal females, thin, pale vaginal mucosa without rugae and pH > 6.0 indicate estrogen deficiency. The presence of cervical mucus with
spinnbarkeit (a stringy, stretchy quality) usually indicates adequate estrogen .
General examination focuses on evidence of virilization, including hirsutism, temporal balding, acne, voice deepening, increased muscle mass, clitoromegaly (clitoral enlargement), and
defeminization (a decrease in previously normal secondary sexual characteristics, such as decreased breast size and vaginal atrophy). Hypertrichosis (excessive growth of hair on the extremities, head,
and back), which is common in some families, is differentiated from true hirsutism, which is characterized by excess hair on the upper lip and chin and between the breasts. Skin discoloration (eg,
yellow due to jaundice or carotenemia, black patches due to acanthosis nigricans) should be noted.
Red flags
15. Evaluation of primary amenorrhea a .
aNormal values are
DHEAS: 250–300 ng/dL (0.7–0.8 µmol/L)
FSH: 5‒20 IU/L
LH: 5‒40 IU/L
Karyotype (female): 46,XX
Prolactin: 100 ng/mL
Testosterone: 20–80 ng/dL (0.7–2.8 nmol/L)
bSome clinicians measure LH levels when they measure FSH levels or when FSH levels are equivocal.
cIf patients have primary amenorrhea and normal secondary sexual characteristics, testing should
begin with pelvic ultrasonography to check for congenital anatomic genital tract obstruction.
dConstitutional delay of growth and puberty is possible.
ePossible diagnoses include functional hypothalamic chronic anovulation and genetic disorders (eg,
congenital gonadotropin-releasing hormone deficiency, Prader-Willi syndrome).
fPossible diagnoses include Cushing syndrome, exogenous androgens, congenital adrenal virilism,
and polycystic ovary syndrome.
gPossible diagnoses include Turner syndrome and disorders characterized by Y chromosome material.
hPublic hair may be sparse.
DHEAS = dehydroepiandrosterone sulfate; FSH = follicle-stimulating
16. Evaluation of secondary amenorrhea.
*Some clinicians simultaneously measure FSH and LH
levels.
†Clinicians should check for the presence of Y
chromosome and Fragile X syndrome.
‡Although these values are representative, normal
ranges may vary between laboratories.
DHEAS = dehydroepiandrosterone sulfate; FSH =
follicle-stimulating hormone; LH = luteinizing
hormone; PCOS = polycystic ovary syndrome; TSH =
thyroid-stimulating hormone.
17. If symptoms or signs suggest a specific disorder, specific tests may be indicated regardless of what an algorithm recommends. For example,
patients with abdominal striae, moon facies, a buffalo hump, truncal obesity, and thin extremities should be tested for Cushing syndrome.
Patients with headaches and visual field defects or evidence of pituitary dysfunction require brain MRI.
If clinical evaluation suggests a chronic disease, liver and kidney function tests are done, and ESR is determined.
Often, testing includes measurement of hormone levels; total serum testosterone or dehydroepiandrosterone sulfate (DHEAS) levels are
measured only if signs of virilization are present. Certain hormone levels should be remeasured to confirm the results. For example, if serum
prolactin is high, it should be remeasured; if serum FSH is high, it should be remeasured monthly at least twice. Amenorrhea with high FSH
levels (hypergonadotropic hypogonadism) suggests ovarian dysfunction; amenorrhea with low FSH levels (hypogonadotropic hypogonadism)
suggests hypothalamic or pituitary dysfunction.
If patients have secondary amenorrhea without virilization and have normal prolactin and FSH levels and normal thyroid function, a trial of
estrogen and a progestogen to try to stimulate withdrawal bleeding can be done (progesterone challenge test).
The progesterone challenge test begins by giving medroxyprogesterone 5 to 10 mg po once/day or another progestin for 7 to 10 days.
If bleeding occurs, amenorrhea is probably not caused by an endometrial lesion (eg, Asherman syndrome) or outflow tract obstruction, and
the cause is probably hypothalamic-pituitary dysfunction, ovarian insufficiency, or estrogen excess.
If bleeding does not occur, an estrogen (eg, conjugated equine estrogen 1.25 mg, estradiol 2 mg) once/day is given for 21 days, followed
by medroxyprogesterone 10 mg po once/day or another progestin for 7 to 10 days. If bleeding does not occur after estrogen is given, patients
may have an endometrial lesion or outflow tract obstruction. However, bleeding may not occur in patients who do not have these
abnormalities (eg, because the uterus is insensitive to estrogen); thus, the trial using estrogen and progestin may be repeated for
confirmation.
However, because this trial takes weeks and results can be inaccurate, diagnosis of some serious disorders may be delayed significantly; thus,
brain MRI should be considered before or during the trial.
Mildly elevated levels of testosterone or DHEAS suggest polycystic ovary syndrome, but levels can be elevated in women with hypothalamic
or pituitary dysfunction and are sometimes normal in hirsute women with polycystic ovary syndrome. The cause of elevated levels can
sometimes be determined by measuring serum LH. In polycystic ovary syndrome, circulating LH levels are often increased, increasing the
ratio of LH to FSH.
18. Treatment is directed at the underlying disorder; with such treatment,
menses sometimes resume. For example, most abnormalities
obstructing the genital outflow tract are surgically repaired.
If a Y chromosome is present, bilateral oophorectomy is recommended
because risk of ovarian germ cell cancer is increased.
Problems associated with amenorrhea may also require treatment,
including
Inducing ovulation if pregnancy is desired
Treating symptoms and long-term effects of estrogen deficiency (eg,
osteoporosis)
Treating symptoms and managing long-term effects of estrogen excess
(eg, prolonged bleeding, persistent or marked breast tenderness, risk of
endometrial hyperplasia and cancer)
Minimizing hirsutism and long-term effects of androgen excess (eg,
cardiovascular disorders, hypertension)
19. Pathophysiology: Dysmenorrhea
Dysmenorrhea: Menstrual cramps or painful periods
Dysmenorrhea is uterine pain around the time of menses. Pain may
occur with menses or precede menses by 1 to 3 days. Pain tends to peak
24 h after onset of menses and subside after 2 to 3 days. It is usually
sharp but may be cramping, throbbing, or a dull, constant ache; it may
radiate to the legs.
Headache, nausea, constipation or diarrhea, lower back pain, and
urinary frequency are common; vomiting occurs occasionally.
Symptoms of premenstrual syndrome may occur during part or all of
menses.
Sometimes endometrial clots or casts are expelled.
Etiology
Dysmenorrhea can be
Primary (more common)
Secondary (due to pelvic abnormalities)
20. Primary dysmenorrhea
Symptoms cannot be explained by structural gynecologic disorders. Pain is thought to result from uterine contractions
and ischemia, probably mediated by prostaglandins (eg, prostaglandin F2α, a potent myometrial stimulant and
vasoconstrictor) and other inflammatory mediators produced in secretory endometrium and possibly associated with
prolonged uterine contractions and decreased blood flow to the myometrium.
Contributing factors may include the following:
Passage of menstrual tissue through the cervix
A narrow cervical os
A malpositioned uterus
Lack of exercise
Anxiety about menses
Primary dysmenorrhea begins within a year after menarche and occurs almost invariably in ovulatory cycles. The pain
usually begins when menses start (or just before) and persists for the first 1 to 2 days; this pain, described as spasmodic,
is superimposed over constant lower abdominal pain, which may radiate to the back or thigh. Patients may also have
malaise, fatigue, nausea, vomiting, diarrhea, low back pain, or headache.
Risk factors for severe symptoms include the following:
Early age at menarche
Long or heavy menstrual periods
Smoking
A family history of dysmenorrhea
Symptoms tend to lessen with age and after pregnancy.
In about 5 to 15% of women with primary dysmenorrhea, cramps are severe enough to interfere with daily activities and
may result in absence from school or work.
21. Secondary dysmenorrhea
Symptoms are due to pelvic abnormalities. Almost any abnormality or process that can affect the
pelvic viscera can cause dysmenorrhea.
Common causes include
Endometriosis (the most common cause)
Uterine adenomyosis
Fibroids
Less common causes include congenital malformations (eg, bicornuate uterus, subseptate uterus,
transverse vaginal septum), ovarian cysts and tumors, pelvic inflammatory disease, pelvic congestion,
intrauterine adhesions, psychogenic pain, and intrauterine devices (IUDs), particularly copper-
or levonorgestrel-releasing IUDs. Levonorgestrel-releasing IUDs cause less cramping than copper-
releasing IUDs.
In a few women, pain occurs when the uterus attempts to expel tissue through an extremely tight
cervical os (secondary to conization, loop electrosurgical excision procedure [LEEP], cryocautery, or
thermocautery). Pain occasionally results from a pedunculated submucosal fibroid or an endometrial
polyp protruding through the cervix.
Risk factors for severe secondary dysmenorrhea are the same as those for primary.
Secondary dysmenorrhea usually begins during adulthood unless caused by congenital
malformations.
22. Evidence-Based Research
Evaluation
History
History of present illness should cover complete menstrual history, including age at onset of menses, duration and amount of flow, time between menses, variability of timing, and relation of menses
to symptoms. Clinicians should also ask about
The age at which symptoms began
Their nature and severity
Factors that relieve or worsen symptoms (including the effects of contraceptives)
Degree of disruption of daily life
Effect on sexual activity
Presence of pelvic pain unrelated to menses
Review of systems should include accompanying symptoms such as cyclic nausea, vomiting, bloating, diarrhea, and fatigue.
Past medical history should identify known causes, including endometriosis, uterine adenomyosis, or fibroids. Method of contraception should be ascertained, specifically asking about IUD use.
Sexual history should include prior or current history of sexual abuse.
Physical examination
Pelvic examination focuses on detecting causes of secondary dysmenorrhea. The vagina, vulva, and cervix are inspected for lesions and for masses protruding through the cervical os. Structures are
palpated to check for a tight cervical os, prolapsed polyp or fibroid, uterine masses, adnexal masses, thickening of the rectovaginal septum, induration of the cul-de-sac, and nodularity of the uterosacral
ligament.
The abdomen is examined for evidence of peritonitis.
Red flags
The following findings are of particular concern:
New or sudden-onset pain
Unremitting pain
Fever
Vaginal discharge
Evidence of peritonitis
Interpretation of findings
Red flag findings suggest a cause of pelvic pain other than dysmenorrhea.
Primary dysmenorrhea is suspected if
Symptoms begin soon after menarche or during adolescence.
Secondary dysmenorrhea is suspected if
Symptoms begin after adolescence.
Patients have known causes, including uterine adenomyosis, fibroids, a tight cervical os, a mass protruding from the cervical os, or, particularly, endometriosis.
Endometriosis is considered in patients with adnexal masses, thickening of the rectovaginal septum, induration of the cul-de-sac, nodularity of the uterosacral ligament, or, occasionally, nonspecific
vaginal, vulvar, or cervical lesions.
Testing
Testing aims to exclude structural gynecologic disorders. Most patients should have
Pregnancy testing
Pelvic ultrasonography
Intrauterine and ectopic pregnancy are ruled out by pregnancy testing. If pelvic inflammatory disease is suspected, cervical cultures are done.
Pelvic ultrasonography is highly sensitive for pelvic masses (eg, ovarian cysts, fibroids, endometriosis, uterine adenomyosis) and can locate lost and abnormally located IUDs.
If these tests are inconclusive and symptoms persist, other tests are done, such as the following:
Hysterosalpingography or sonohysterography to identify endometrial polyps, submucous fibroids, or congenital abnormalities
MRI to identify other abnormalities, including congenital abnormalities, or, if surgery is planned, to further define previously identified abnormalities
IV pyelography, but only if a uterine malformation has been identified as causing or contributing to the dysmenorrhea
If results of all other tests are inconclusive, hysteroscopy or laparoscopy can be done. Laparoscopy is the most definitive test because it enables clinicians to directly examine all of the pelvis and
reproductive organs and to check for abnormalities.
23. Management
Treatment
Underlying disorders are treated.
General measures
Symptomatic treatment begins with adequate rest and sleep and regular exercise. A low-fat diet and nutritional
supplements such as ω-3 fatty acids, flaxseed, magnesium, vitamin E, zinc, and vitamin B1 are suggested as potentially
effective.
Women with primary dysmenorrhea are reassured about the absence of structural gynecologic disorders.
Drugs
If pain persists, NSAIDs (which relieve pain and inhibit prostaglandins) are typically tried. NSAIDs are usually started
24 to 48 h before and continued until 1 or 2 days after menses begin.
If the NSAID is ineffective, suppression of ovulation with a low-dose estrogen/progestin oral contraceptive may be
tried.
Other hormone therapy, such as danazol, progestins (eg, levonorgestrel, etonogestrel,
depot medroxyprogesterone acetate), gonadotropin-releasing hormone agonists, or a levonorgestrel-releasing IUD,
may decrease dysmenorrheal symptoms.
Periodic adjunctive use of analgesics may be needed.
Other treatments
Hypnosis is being evaluated as treatment. Other proposed nondrug therapies, including acupuncture, acupressure,
chiropractic therapy, and transcutaneous electrical nerve stimulation, have not been well-studied but may benefit
some patients.
For intractable pain of unknown origin, laparoscopic presacral neurectomy or uterosacral nerve ablation has been
efficacious in some patients for as long as 12 mo.
24. Pathophysiology: Dysfunctional
Uterine Bleeding (DUB)
Dysfunctional uterine bleeding (DUB), the most common cause of abnormal uterine
bleeding, occurs most often in women > 45 (> 50% of cases) and in adolescents (20% of
cases).
About 90% of cases are anovulatory; 10% are ovulatory.
During an anovulatory cycle, the corpus luteum does not form. Thus, the normal
cyclical secretion of progesterone does not occur, and estrogen stimulates the
endometrium unopposed. Withoutprogesterone, the endometrium continues to
proliferate, eventually outgrowing its blood supply; it then sloughs incompletely and
bleeds irregularly and sometimes profusely or for a long time. When this abnormal
process occurs repeatedly, the endometrium can become hyperplastic, sometimes with
atypical or cancerous cells.
In ovulatory DUB, progesterone secretion is prolonged; irregular shedding of the
endometrium results, probably because estrogen levels remain low, near the threshold
for bleeding (as occurs during menses). In obese women, ovulatory DUB can occur
if estrogen levels are high, resulting in amenorrhea alternating with irregular or
prolonged bleeding.
Complications
Chronic bleeding may cause iron deficiency anemia.
If DUB is due to chronic anovulation, infertility may also be present.
25. Etiology
Anovulatory DUB can result from any disorder or condition
that causes anovulation (see Table: Some Causes of Anovulatory
Amenorrhea). Anovulation is most often
Secondary to polycystic ovary syndrome
Idiopathic (sometimes occurring when gonadotropin levels are
normal)
Sometimes anovulation results from hypothyroidism.
During perimenopause, DUB may be an early sign of ovarian
insufficiency or failure; follicles are still developing but, despite
increasing levels of follicle-stimulating hormone (FSH), do not
produce enough estrogen to trigger ovulation. About 20% of
women with endometriosishave anovulatory DUB due to
unknown mechanisms.
26. Ovulatory DUB may occur in
Polycystic ovary syndrome
(because progesterone secretion is prolonged)
Endometriosis, which does not affect ovulation
Other causes are a short follicular phase and luteal
phase dysfunction (due to
inadequate progesterone stimulation of the
endometrium); a rapid decrease in estrogen before
ovulation can cause spotting.
27. Symptoms and Signs
Compared with typical menses, bleeding may
Occur more frequently (menses < 21 days apart—polymenorrhea)
Involve more blood loss (> 7 days or > 80 mL) during menses (menorrhagia, or
hypermenorrhea)
Occur frequently and irregularly between menses (metrorrhagia)
Involve more blood loss during menses and frequent and irregular bleeding
between menses (menometrorrhagia)
Ovulatory DUB tends to cause excessive bleeding during regular menstrual
cycles. Women may have other symptoms of ovulation, such as premenstrual
symptoms, breast tenderness, midcycle cramping pain (mittelschmerz), a
change in basal body temperature after ovulation (see Ovulatory Dysfunction),
and sometimes dysmenorrhea.
Anovulatory DUB occurs at unpredictable times and in unpredictable
patterns and is not accompanied by cyclic changes in basal body temperature.
28. Evidence-Based Research
Diagnosis
Exclusion of other potential causes
CBC, pregnancy test, and hormone measurement (eg, thyroid-stimulating hormone [TSH], prolactin)
Usually transvaginal ultrasonography and endometrial sampling
Often sonohysterography and/or hysteroscopy
Women should be evaluated for DUB when the amount or timing of vaginal bleeding is inconsistent with normal menses.
DUB is a diagnosis of exclusion; other conditions that can cause similar bleeding must be excluded (see Vaginal Bleeding). Pregnancy should be excluded, even in young adolescents and
perimenopausal women. Coagulation disorders should be considered, particularly in adolescents who have anemia or require hospitalization for bleeding. Regular cycles with prolonged or excessive
bleeding (possible ovulatory DUB) suggest structural abnormalities.
Laboratory testing
Several tests are typically done:
A urine or blood pregnancy test
CBC
TSH, prolactin, and progesterone levels
All women of reproductive age should have a pregnancy test.
CBC is routinely done. However, Hct may be normal in women who report heavy bleeding, or anemia may be severe in women who regularly have heavy periods. The serum ferritin level, which reflects
body iron stores, is measured if women have chronic, heavy bleeding.
Thyroid-stimulating hormone levels are usually measured, and prolactin levels are measured, even when galactorrhea is absent, because thyroid disorders and hyperprolactinemia are common causes of
abnormal bleeding.
To determine whether bleeding is anovulatory or ovulatory, some clinicians measure serum progesterone levels during the luteal phase (after day 14 of a normal menstrual cycle or after basal body
temperature increases, as occurs during this phase). A level of ≥ 3 ng/mL (≥9.75 nmol/L) suggests that ovulation has occurred.
Other tests are done depending on results of the history and physical examination and include the following:
Coagulation tests if women have risk factors for coagulation disorders, bruising, or hemorrhage
Liver function tests if a liver disorder is suspected
Testosterone and dehydroepiandrosterone sulfate (DHEAS) levels if polycystic ovary syndrome is suspected
Follicle-stimulating hormone (FSH) and estradiol levels if primary ovarian insufficiency is possible
A cervical cancer screening test (eg, Papanicolaou [Pap] test, HPV test) if results are out-of-date
Testing for Neisseria gonorrhea and Chlamydia sp if pelvic inflammatory disease or cervicitis is suspected
If all clinically indicated tests are normal, the diagnosis is dysfunctional uterine bleeding.
Additional testing
Transvaginal ultrasonography is done if women have any of the following:
Age ≥ 35
Risk factors for endometrial cancer (eg, obesity, diabetes, hypertension, polycystic ovary syndrome, chronic eugonadal anovulation, hirsutism, other conditions associated with prolonged
unopposed estrogen exposure)
Bleeding that continues despite use of empiric hormone therapy
Pelvic organs that cannot be examined adequately during the physical examination
Clinical evidence that suggests abnormalities in the ovaries or uterus
These criteria include almost all women with dysfunctional uterine bleeding.
Transvaginal ultrasonography can detect structural abnormalities, including most polyps, fibroids, other masses, endometrial cancer, and any areas of focal thickening in the endometrium. If focal
thickening is detected, further testing may be needed to identify smaller intrauterine masses (eg, small endometrial polyps, submucous myomas). Sonohysterography (ultrasonography after saline is
infused into the uterus) is useful in evaluating such abnormalities; it can be used to determine whether hysteroscopy, a more invasive test, is indicated and to plan resection of intrauterine masses. Or
hysteroscopy may be done without sonohysteroscopy.
In endometrial sampling , only about 25% of the endometrium is analyzed, but sensitivity for detecting abnormal cells is about 97%. This test is usually recommended to rule out hyperplasia or cancer
in women with any of the following:
Age > 35 yr with one or more risk factors for endometrial cancer (see above)
Age < 35 yr with multiple risk factors for endometrial cancer (see above)
Bleeding that is persistent, irregular, or heavy
Irregular cycles that suggest chronic anovulatory bleeding
29. Management
Treatment
Control of bleeding, usually with an NSAID, tranexamic acid, or hormone therapy
In women with endometrial hyperplasia, prevention of endometrial cancer
Bleeding
Nonhormonal treatments have fewer risks and adverse effects than hormone therapy and can be given intermittently, when bleeding occurs. They are used mainly for heavy regular bleeding
(menorrhagia). Choices include
NSAIDs, which reduce bleeding by 25 to 35% and relieve dysmenorrhea by reducing prostaglandin levels
Tranexamic acid, which inhibits plasminogen activator, reducing menstrual blood loss by 40 to 60%
Hormone therapy (eg, oral contraceptives, progestogens) is often tried first in perimenopausal women. This therapy does the following:
Suppresses endometrial development
Reestablishes predictable bleeding patterns
Decreases menstrual flow
Hormone therapy is usually given until bleeding has been controlled for a few months.
Oral contraceptives (OCs) are commonly given. OCs, used cyclically or continuously, can control dysfunctional bleeding. Limited data suggest that they do the following:
Decrease menstrual blood loss by 40 to 50%
Decrease breast tenderness and dysmenorrhea
Decrease risk of uterine and ovarian cancer
Combination formulations consisting of an estrogen and a progestin or a progestin alone may be used. Risks of an OC depend on the type of OC and on patient factors.
Progesterone or another progestin can be used alone in the following cases:
Estrogen is contraindicated (eg, for patients with cardiovascular risk factors or prior deep vein thrombosis).
Estrogen is declined by the patient.
Combination OCs are ineffective after about 3 mo of use.
Withdrawal bleeding may be more predictable with cyclic progestin therapy (medroxyprogesterone acetate 10 mg/day po ornorethindrone acetate 2.5 to 5 mg/day po) given for 21 days/mo than with a
combination OC. Cyclic natural (micronized) progesterone 200 mg/day for 21 days/mo may be used, particularly if pregnancy is possible; however, it may cause drowsiness and does not decrease blood
loss as much as a progestin.
If patients using cyclic progestins or progesterone wish to prevent pregnancy, contraception should be used. Contraceptive options include
A levonorgestrel-releasing intrauterine device (IUD): It is effective in up to 97% by 6 mo, provides contraception, and relieves dysmenorrhea.
Depot medroxyprogesterone acetate injections: They cause amenorrhea and provide contraception but may cause irregular spotting and reversible bone loss.
Other treatments that are occasionally used to treat DUB include
Danazol: It reduces menstrual blood loss (by causing endometrial atrophy) but has many androgenic adverse effects, which may be lessened by using lower doses or a vaginal formulation. To be
effective, danazol must be taken continuously, usually for about 3 mo. It is usually used when other forms of therapy are contraindicated.
Gonadotropin-releasing hormone (GnRH) agonists: These drugs suppress ovarian hormone production and cause amenorrhea; they are used to shrink fibroids or the endometrium preoperatively.
However, their hypoestrogenic adverse effects (eg, bone loss) limit their use.
Desmopressin: It is used as a last resort to treat DUB in patients who have a coagulation disorder; it rapidly increases levels of von Willebrand factor and factor VIII for about 6 h.
Ergot derivatives are not recommended for treatment of DUB because they are rarely effective.
If pregnancy is desired and bleeding is not heavy, ovulation induction with clomiphene (50 mg po on days 5 through 9 of the menstrual cycle) can be tried.
Hysteroscopy with D & C may be therapeutic as well as diagnostic; it may be the treatment of choice when anovulatory bleeding is severe or when hormone therapy is ineffective. Structural causes
such as polyps or fibroids may be identified or removed during hysteroscopy. This procedure may decrease bleeding but, in some women, causes amenorrhea due to endometrial scarring (Asherman
syndrome).
Endometrial ablation (eg, laser, rollerball, resectoscopic, thermal, or freezing) may help control bleeding in 60 to 80%. Ablation is less invasive than hysterectomy, and the recovery time is shorter.
Ablation may be repeated if heavy bleeding recurs after ablation is initially effective. If this treatment does not control bleeding or if bleeding continues to recur, the cause may be adenomyosis and thus
is not DUB. Endometrial ablation does not prevent pregnancy. Pregnancy rates may be as high as 5% after ablation. Ablation causes scarring which may make sampling the endometrium difficult later.
Hysterectomy , abdominal or vaginal, may be recommended for patients who decline hormone therapy or who, despite other treatments, have symptomatic anemia or poor quality of life caused by
persistent, irregular bleeding.
Emergency measures are needed only rarely, when bleeding is very heavy. Patients are stabilized hemodynamically with IV crystalloid fluid, blood products, and other measures as needed. If bleeding
persists, a bladder catheter is inserted into the uterus and inflated with 30 to 60 mL of water to tamponade the bleeding. Once patients are stable, hormone therapy is used to control bleeding.
Very rarely, in patients with very heavy bleeding due to anovulatory DUB, conjugated estrogens 25 mg IV q 4 to 6 h for a total of 4 doses may be used. This therapy stops bleeding in about 70% of
patients but increases risk of thrombosis. Immediately afterward, patients are given a combination OC, which may be continued until bleeding has been controlled for a few months.
30. Pathophysiology: Premenstrual
Syndrome (PMS)
Premenstrual Syndrome (PMS): Physical and
psychologic symptoms that occur before the start of a
period
Premenstrual syndrome (PMS) is characterized by
irritability, anxiety, emotional lability, depression, edema,
breast pain, and headaches, occurring during the 7 to 10
days before and usually ending a few hours after onset of
menses. Diagnosis is clinical, often based on the patient’s
daily recording of symptoms. Treatment is symptomatic
and includes diet, drugs, and counseling.
About 20 to 50% of women of reproductive age have PMS;
about 5% have a severe form of PMS called premenstrual
dysphoric disorder.
31. Evidence-Based Research
Etiology
The cause is unclear.
Possible causes or contributing factors include
Multiple endocrine factors (eg, hypoglycemia, other changes in carbohydrate metabolism, hyperprolactinemia, fluctuations in levels of
circulating estrogen and progesterone, abnormal responses to estrogen and progesterone, excess aldosterone or ADH)
A genetic predisposition
Serotonin deficiency
Possibly magnesium and calcium deficiencies
Estrogen and progesterone can cause transitory fluid retention, as can excess aldosterone or ADH.
Serotonin deficiency is thought to contribute because women who are most affected by PMS have lower serotonin levels and because SSRIs
(which increase serotonin) sometimes relieve symptoms of PMS.
Magnesium and calcium deficiencies may contribute.
Symptoms and Signs
Type and intensity of symptoms vary from woman to woman and from cycle to cycle. Symptoms last a few hours to ≥ 10 days, usually ending
when menses begins. Symptoms may become more severe during stress or perimenopause. In perimenopausal women, symptoms may
persist until after menses.
The most common symptoms are irritability, anxiety, agitation, anger, insomnia, difficulty concentrating, lethargy, depression, and severe
fatigue. Fluid retention causes edema, transient weight gain, and breast fullness and pain. Pelvic heaviness or pressure and backache may
occur. Some women, particularly younger ones, have dysmenorrhea when menses begins.
Other nonspecific symptoms may include headache, vertigo, paresthesias of the extremities, syncope, palpitations, constipation, nausea,
vomiting, and changes in appetite. Acne and neurodermatitis may also occur. Existing skin disorders may worsen, as may respiratory
problems (eg, allergies, infection) and eye problems (eg, visual disturbances, conjunctivitis).
Premenstrual dysphoric disorder (PMDD)
Some women have severe PMS symptoms that occur regularly and only during the 2nd half of the menstrual cycle; symptoms end with
menses or shortly after. Mood is markedly depressed, and anxiety, irritability, and emotional lability are pronounced. Suicidal thoughts may
be present. Interest in daily activities is greatly decreased.
In contrast to PMS, PMDDcauses symptoms that are severe enough to interfere with routine daily activities or overall functioning. PMDD is
a severely distressing, disabling, and often underdiagnosed.
32. Diagnosis
For PMS, patient’s report of symptoms
For PMDD, clinical criteria
PMS is diagnosed based on physical symptoms (eg, bloating, weight gain, breast tenderness, swelling of hands and feet). Women may be
asked to record their symptoms daily. Physical examination and laboratory testing are not helpful.
If PMDD is suspected, women are asked to rate their symptoms daily for ≥ 2 cycles to determine whether severe symptoms occur regularly.
For PMDD to be diagnosed, women must have ≥ 5 of the following symptoms for most of the week before menses, and symptoms must
become minimal or absent during the week after menstruation. Symptoms must include at least one of the following:
Marked mood swings (eg, sudden sadness)
Marked irritability or anger or increased interpersonal conflicts
Marked depressed mood, feelings of hopelessness, or self-deprecating thoughts
Marked anxiety, tension, or an on-edge feeling
In addition, ≥ 1 of the following must be present:
Decreased interest in usual activities, possibly causing withdrawal
Difficulty concentrating
Low energy or fatigue
Marked changes in appetite, overeating, or specific food cravings
Insomnia or hyperinsomnia
Feelings of being overwhelmed or out of control
Physical symptoms associated with PMS (eg, breast tenderness, edema)
Also, the symptom pattern must have occurred for most of the previous 12 mo, and symptoms must be severe enough to interfere with daily
activities and function.
Patients with symptoms of depression are evaluated using a depression inventory or are referred to a mental health care practitioner for
formal evaluation.
33. Management
Treatment
General measures
Sometimes SSRIs or hormonal manipulation
PMS can be difficult to treat. No single treatment has proven efficacy for all women, and few woman have complete relief with any single type of treatment. Treatment can thus
require trial and error, as well as patience.
General measures
Treatment is symptomatic, beginning with adequate rest and sleep, regular exercise, and activities that are relaxing. Regular exercise may help alleviate bloating as well as
irritability, anxiety, and insomnia. Yoga helps some women.
Dietary changes—increasing protein, decreasing sugar, consuming complex carbohydrates, and eating smaller meals more frequently—may help, as may counseling, avoiding
stressful activities, relaxation training, light therapy, sleep adjustments, and cognitive-behavioral therapy. Other possible strategies include avoiding certain foods and drinks
(eg, cola, coffee, hot dogs, potato chips, canned goods) and eating more of others (eg, fruits, vegetables, milk, high-fiber foods, low-fat meats, foods high in calcium and vitamin
D). The beneficial effects of dietary supplements have not been substantiated.
Drugs
NSAIDs can help relieve aches, pains, and dysmenorrhea.
SSRIs (eg, fluoxetine 20 mg po once/day) are the drugs of choice for relief of anxiety, irritability, and other emotional symptoms, particularly if stress cannot be avoided. SSRIs
effectively relieve symptoms of PMS and PMDD. Continuous dosing is more effective than intermittent dosing. No SSRI appears to be more effective than another.
Clomipramine, given for the full cycle or a half-cycle, effectively relieves emotional symptoms, as does nefazodone, a serotonin-norepinephrine reuptake inhibitor (SNRI).
Anxiolytics may help but are usually less desirable because dependence or addiction is possible. Buspirone, which may be given throughout the cycle or during the late luteal
phase, helps relieve symptoms of PMS and PMDD. Adverse effects include nausea, headache, anxiety, and dizziness.
For some women, hormonal manipulation is effective. Options include
Oral contraceptives
Progesterone by vaginal suppository (200 to 400 mg once/day)
An oral progestogen (eg, micronized progesterone 100 mg at bedtime) for 10 to 12 days before menses
A long-acting progestin (eg, medroxyprogesterone 200 mg IM q 2 to 3 mo)
Women who choose to use an oral contraceptive for contraception can take drospirenone plus ethinyl estradiol. However, risk of venous thromboembolism may be increased.
Rarely, for very severe or refractory symptoms, a gonadotropin-releasing hormone agonist (eg, leuprolide 3.75 mg IM, goserelin 3.6 mg sc q mo) with low-dose
estrogen/progestin (eg, oral estradiol 0.5 mg once/day plus micronized progesterone 100 mg at bedtime) is given to minimize cyclic fluctuations.
Fluid retention may be relieved by reducing sodium intake and taking a diuretic (eg, spironolactone 100 mg po once/day) just before symptoms are expected. However,
minimizing fluid retention and taking a diuretic do not relieve all symptoms and may have no effect.
Bromocriptine and monoamine oxidase inhibitors are not useful.
Surgery
In women with severe symptoms, bilateral oophorectomy may alleviate symptoms because it eliminates menstrual cycles; hormone replacement therapy is then indicated until
about age 51 (when menopause usually occurs).
34. Pathophysiology: Endometriosis
In endometriosis, functioning endometrial tissue is implanted outside the
uterine cavity. Symptoms depend on location of the implants and may include
dysmenorrhea, dyspareunia, infertility, dysuria, and pain during defecation.
Severity of symptoms is not related to disease stage. Diagnosis is by biopsy,
usually via laparoscopy. Treatments include anti-inflammatory drugs, drugs to
suppress ovarian function and endometrial tissue growth, surgical ablation and
excision of endometriotic implants, and, if disease is severe and no childbearing
is planned, hysterectomy plus oophorectomy.
Endometriosis is usually confined to the peritoneal or serosal surfaces of pelvic organs,
commonly the ovaries, broad ligaments, posterior cul-de-sac, and uterosacral ligaments.
Less common sites include the fallopian tubes, serosal surfaces of the small and large
intestines, ureters, bladder, vagina, cervix, surgical scars, pleura, and pericardium.
Bleeding from peritoneal implants is thought to initiate inflammation, followed by fibrin
deposition, adhesion formation, and, eventually, scarring, which distorts peritoneal
surfaces of organs and pelvic anatomy.
Reported prevalence varies but is probably about 6 to 10% in all women, 25 to 50% in
infertile women, and 75 to 80% in women with chronic pelvic pain. Average age at
diagnosis is 27, but endometriosis also occurs among adolescents. Incidence is increased
in women who have 1st-degree relatives with endometriosis, who delay childbearing, who
have shortened menstrual cycles (< 27 days) with menses that are heavy and prolonged
abnormally long (> 8 days), or who have müllerian duct defects.
35. Evidence-Based Research
Etiology and Pathophysiology
The most widely accepted hypothesis is that endometrial cells are transported from the uterine cavity and subsequently become implanted at ectopic sites. Retrograde flow of
menstrual tissue through the fallopian tubes could transport endometrial cells intra-abdominally; the lymphatic or circulatory system could transport endometrial cells to
distant sites (eg, the pleural cavity). Another hypothesis is coelomic metaplasia: Coelomic epithelium is transformed into endometrium-like glands.
Microscopically, endometriotic implants consist of glands and stroma identical to intrauterine endometrium. These tissues containestrogen and progesterone receptors and
thus usually grow, differentiate, and bleed in response to changes in hormone levels during the menstrual cycle; also, these tissues can produce estrogen and prostaglandins.
Implants may become self-sustaining or regress, as may occur during pregnancy (probably because of progesterone levels are high). Ultimately, the implants cause
inflammation and increase the number of activated macrophages and the production of proinflammatory cytokines.
The increased incidence in 1st-degree relatives of women with endometriosis suggests that heredity is a factor.
In patients with severe endometriosis and distorted pelvic anatomy, the infertility rate is high, possibly because the distorted anatomy interferes with mechanisms of ovum
pickup and tubal transport. Some patients with minimal endometriosis and normal pelvic anatomy are also infertile; reasons for impaired fertility are unclear but may include
the following:
Increased incidence of luteinized unruptured ovarian follicle syndrome (trapped oocyte)
Increased peritoneal prostaglandin production or peritoneal macrophage activity that may affect sperm and oocyte function
Nonreceptive endometrium (because of progesterone resistance, luteal phase dysfunction, or other abnormalities)
Potential protective factors seem to be multiple pregnancies, use of low-dose oral contraceptives (continuous or cyclic), and regular exercise (especially if begun before age 15,
if done for > 4 h/wk, or both).
Symptoms and Signs
Cyclic midline pelvic pain, specifically pain preceding or during menses and during sexual intercourse, is typical and can be progressive. Adnexal masses and infertility are also
typical. Intermenstrual bleeding is possible. Some women with extensive endometriosis are asymptomatic; some with minimal disease have incapacitating pain. Dysmenorrhea
is an important diagnostic clue, particularly if it begins after several years of relatively pain-free menses. Symptoms often lessen or resolve during pregnancy.
Symptoms can vary depending on location of implants.
Large intestine: Pain during defecation, abdominal bloating, diarrhea or constipation, or rectal bleeding during menses
Bladder: Dysuria, hematuria, suprapubic pain (particularly during urination), or a combination
Ovaries: Formation of an endometrioma (a 2- to 10-cm cystic mass localized to an ovary), which occasionally ruptures or leaks, causing acute abdominal pain and peritoneal
signs
Adnexal structures: Formation of adnexal adhesions, resulting in a pelvic mass or pain
Extrapelvic structures: Vague abdominal pain (sometimes)
Pelvic examination may be normal, or findings may include a retroverted and fixed uterus, enlarged ovaries, fixed ovarian masses, thickened rectovaginal septum, induration of
the cul-de-sac, nodules on the uterosacral ligament, and/or adnexal masses. Rarely, lesions can be seen on the vulva or cervix or in the vagina, umbilicus, or surgical scars.
36. Diagnosis
Biopsy, usually laparoscopic
Sometimes imaging tests (to follow progression) but not for diagnosis
Diagnosis is suspected based on typical symptoms but must be confirmed by biopsy, usually via pelvic laparoscopy but
sometimes via laparotomy, vaginal examination, sigmoidoscopy, or cystoscopy. Macroscopic appearance (eg, clear, red,
brown, black) and size of implants vary during the menstrual cycle. However, typically, areas of endometriosis on the
pelvic peritoneum are punctate red, blue, or purplish brown spots that are > 5 mm, often called powder burn lesions.
Microscopically, both endometrial glands and stroma must be present to diagnose endometriosis.
Imaging tests (eg, ultrasonography, barium enema, IV urography, CT, MRI) are not specific or adequate for diagnosis.
However, they sometimes show the extent of endometriosis and thus can be used to monitor the disorder once it is
diagnosed. The serum cancer antigen 125 level may be elevated, but obtaining this level is usually not helpful in
diagnosis or management. Testing for other infertility disorders may be indicated (see page Infertility).
Staging the disorder helps physicians formulate a treatment plan and evaluate response to therapy. According to the
American Society for Reproductive Medicine, endometriosis may be classified as stage I (minimal), II (mild), III
(moderate), or IV (severe), based on number, location, and depth of implants, and presence of endometriomas and
filmy or dense adhesions
A new staging system called the endometriosis fertility index (EFI) has been developed for women with endometriosis-
associated infertility; this system can help predict pregnancy rates after various treatments. Factors used to score the
EFI include the woman's age, the number of years she has been infertile, history or absence of prior pregnancies, and
the least-function score for both fallopian tubes, fimbria, and ovaries, as well as the American Society for Reproductive
Medicine endometriosis (lesion and total) scores.
37. Stages of Endometriosis
Stage
Classification
Description
I
Minimal
A few superficial implants
II
Mild
More and slightly deeper implants
III
Moderate
Many deep implants, small endometriomas on one or both ovaries, and some filmy
adhesions
IV
Severe
Many deep implants, large endometriomas on one or both ovaries, and many dense
adhesions, sometimes with the rectum adhering to the back of the uterus
38. Management
Treatment
NSAIDs for discomfort
Drugs to suppress ovarian function
Conservative surgical resection or ablation of endometriotic tissue, with or without drugs
Total abdominal hysterectomy with bilateral salpingo-oophorectomy if disease is severe and patient has completed childbearing
Symptomatic treatment begins with NSAIDs. More definitive treatment must be individualized based on the patient's age, symptoms, and desire to preserve fertility and on the
extent of the disorder.
Drugs and conservative surgery are symptomatic treatments; in most patients, endometriosis recurs within 6 mo to 1 yr after treatment is stopped unless ovarian function is
permanently and completely ablated.
Drug therapy
Drugs that suppress ovarian function inhibit the growth and activity of endometriotic implants. These drugs include continuous oral contraceptives (commonly used),
progestins, gonadotropin-releasing hormone (GnRH) agonists, and danazol (see Table: Drugs Used to Treat Endometriosis).
GnRH agonists temporarily suppress estrogen production; however, treatment is limited to ≤ 6 mo because long-term use may result in bone loss. If treatment lasts > 4 to 6
mo, a progestin may be used concurrently (as add-back therapy) to minimize bone loss.
Danazol , a synthetic androgen and an antigonadotropin, inhibits ovulation. However, its androgenic adverse effects limit its use.
Cyclic or continuous oral contraceptives given after danazol or GnRH agonists may slow disease progression and are warranted for women who wish to delay childbearing.
An aromatase inhibitor plus a combination contraceptive can be considered if none of these drugs is effective; such treatment is sometimes successful.
Drug treatment does not change fertility rates in women with minimal or mild endometriosis.
Surgery
Most women with moderate to severe endometriosis are treated most effectively by ablating or excising as many implants as possible while maintaining pelvic anatomy and
preserving fertility as much as possible. Specific indications for surgery include
Presence of endometriomas
Significant pelvic adhesions
Fallopian tube obstruction
Incapacitating pelvic pain
A desire to preserve fertility
Lesions are usually removed via a laparoscope; peritoneal or ovarian lesions can sometimes be electrocauterized, excised, or vaporized with a laser. Endometriomas should be
removed because removal prevents recurrence more effectively than drainage. After this treatment, fertility rates are inversely proportional to the severity of endometriosis. If
resection is incomplete, GnRH agonists are sometimes given during the perioperative period, but whether these drugs increase fertility rates is unclear. Laparoscopic resection
of the uterosacral ligaments with electrocautery or a laser may reduce midline pelvic pain. If women have deep rectovaginal endometriosis, continuous progestin therapy is the
most effective treatment.
Hysterectomy should usually be reserved for patients who have intractable pelvic pain and who have completed childbearing. Hysterectomy is done in addition to
oophorectomy to remove adhesions or implants that adhere to the uterus or cul-de-sac. If women < 50 require hysterectomy with oophorectomy, supplemental estrogen should
be considered (eg, to prevent menopausal symptoms). However, concomitant continuous progestin therapy (eg, medroxyprogesterone acetate 2.5 mg po once/day) is often
recommended because if estrogen is given alone, residual tissue may grow, resulting in recurrence rates of up to 40%. If symptoms persist after oophorectomy in women > 50,
continuous progestin therapy alone (medroxyprogesterone acetate 2.5 mg po once/day, micronized progesterone 100 to 200 mg po at bedtime) can be tried.
39. Drugs Used to Treat Endometriosis
Drug
Dosage
Adverse Effects
Drug
Dosage
Adverse Effects
Combination estrogen/progestin oral contraceptive
Ethinyl estradiol 20 mcg plus a progestin
Continuous, prolonged use (1 tablet once/day for 4–6 cycles, then stopped for 4 days) or cyclic use (as directed for contraception, usually not taken for several days to 1 wk each mo)
Abdominal swelling, breast tenderness, increased appetite, edema, nausea, breakthrough bleeding, deep venous thrombosis, MI, stroke, peripheral vascular disease
Progestins
Levonorgestrel-releasing intrauterine device (IUD)
About 20 mcg/day, decreasing progressively over 5 yr to 10 mcg (delivered by IUD)
Irregular uterine bleeding, sometimes amenorrhea (developing over time), weight gain
Medroxyprogesteroneacetate
20–30 mg po once/day for 6 mo, followed by 100 mg IM q 2 wk for 2 mo, then 200 mg IM monthly for 4 mo
Breakthrough bleeding, emotional lability, depression, atrophic vaginitis, MI, stroke, peripheral vascular disease, weight gain
Norethindroneacetate
2.5–5 mg po at bedtime
Irregular uterine bleeding, emotional lability, depression, weight gain
Androgen
Danazol
100–400 mg po bid for 3–6 mo
Weight gain, acne, lowering of voice, hirsutism, hot flushes, atrophic vaginitis, edema, muscle cramps, breakthrough bleeding, decreased breast size, emotional lability, liver dysfunction, carpal tunnel
syndrome, adverse effects on lipid levels
GnRH agonists*
Leuprolide
†
1 mg sc once/day
Hot flushes, atrophic vaginitis, bone demineralization, emotional lability, headaches, weakness, myalgias
Leuprolide depot
3.75 mg IM q 28 days
or
11.25 mg IM q 3 mo
Same as for sc.
Nafarelin
200–400 mcg intranasally bid
Hot flushes, atrophic vaginitis, bone demineralization, emotional lability, headaches, acne, decreased libido, vaginal dryness, leukopenia
*Treatment is limited to ≤ 6 mo.
†Leuprolide is often given with a progestin such as norethindrone acetate (2.5–5 mg po once/day) to prevent bone loss during treatment.
GnRH = gonadotropin-releasing hormone.
40. Polycystic Ovary Syndrome
Polycystic ovary syndrome is a clinical syndrome characterized by mild obesity, irregular menses or
amenorrhea, and signs of androgen excess (eg, hirsutism, acne).
In most patients, the ovaries contain multiple cysts.
Diagnosis is by pregnancy testing, hormone measurement, and imaging to exclude a virilizing tumor.
Treatment is symptomatic.
Polycystic ovary syndrome (PCOS) occurs in 5 to 10% of women. In the US, it is the most common cause of infertility.
PCOS is usually defined as a clinical syndrome, not by the presence of ovarian cysts. But typically, ovaries contain many
2- to 6-mm follicular cysts and sometimes larger cysts containing atretic cells. Ovaries may be enlarged with smooth,
thickened capsules or may be normal in size.
This syndrome involves anovulation or ovulatory dysfunction and androgen excess of unclear etiology. However, some
evidence suggests that patients have a functional abnormality of cytochrome P450c17 affecting 17-hydroxylase (the
rate-limiting enzyme in androgen production); as a result, androgen production increases.
Polycystic Ovary Syndrome (PCOS)
Complications
Polycystic ovary syndrome has several serious complications.
Estrogen levels are elevated, increasing risk of endometrial hyperplasia and, eventually, endometrial cancer.
Androgen levels are often elevated, increasing the risk of metabolic syndrome and causinghirsutism. Hyperinsulinemia
due to insulin resistance may be present and may contribute to increased ovarian production of androgens. Over the
long term, androgen excess increases the risk of cardiovascular disorders, including hypertension. Risk of androgen
excess and its complications may be just as high in women who are not overweight as in those who are.
41. Pelvic Congestion Syndrome
Pelvic congestion syndrome is chronic pain exacerbated by standing or sexual intercourse in women who
have varicose veins in or near the ovaries.
Pelvic congestion syndrome is a common cause of chronic pelvic pain. Varicose veins and venous insufficiency are
common in the ovarian veins but are often asymptomatic. Why some women develop symptoms is unknown.
Symptoms and Signs
Pelvic pain develops after pregnancy. Pain tends to worsen with each subsequent pregnancy.
Typically, the pain is a dull ache, but it may be sharp or throbbing. It is worse at the end of the day (after women have
been sitting or standing a long time) and is relieved by lying down. The pain is also worse during or after sexual
intercourse. It is often accompanied by low back pain, aches in the legs, and abnormal menstrual bleeding.
Some women occasionally have a clear or watery discharge from the vagina.
Other symptoms may include fatigue, mood swings, headaches, and abdominal bloating.
Pelvic examination detects tender ovaries and cervical motion tenderness.
Diagnosis
Clinical criteria
Ovarian varicosities, detected during imaging
Diagnosis requires that pain be present for > 6 mo and that ovaries be tender when examined.
Ultrasonography is done but may not show varicosities in women when they are recumbent.
Some experts recommend additional tests (eg, venography, CT, MRI, magnetic resonance venography) if necessary to
confirm pelvic varicosities.
If pelvic pain is troublesome and the cause has not been identified, laparoscopy is done.
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45. Introduction to Menstrual Abnormalities, JoAnn
V. Pinkerton, MD 2016 Merck Sharp & Dohme Corp.,
a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
http://www.merckmanuals.com/
