Disorders of the menstrual cycle include (1) amenorrhea (lack
of menstrual bleeding), which may be primary amenorrhea (ie, the
failure of onset of menstrual periods by age 16) or secondary amenorrhea
(ie, the lack of menstrual periods for 6 months in a previously
menstruating woman); (2) dysmenorrhea (pain and other
symptoms accompanying menstruation); or (3) menorrhagia (excessive
vaginal bleeding) or metrorrhagia (irregular or abnormally
protracted vaginal bleeding).
The cause of amenorrhea can be traced to one of four broad categories
of conditions (Table 22–5):
Table 22–5 Causes of Amenorrhea. |Favorite Table|Download (.pdf)
Table 22–5 Causes of Amenorrhea.
|Category||Common Causes||Pathophysiologic Mechanisms||How to Make a Diagnosis||Intervention|
|Normal physiologic processes||Pregnancy||Sustained high estrogen and progesterone||Serum β-hCG, history||Prenatal care|
|Menopause||Lack of estrogen||Clinical diagnosis||Recommendations for osteoporosis prevention|
|Disorders of the uterus and outflow tract||Disorders of sexual development||Excessive androgen exposure||Physical examination||Surgical treatment|
|Congenital anomalies (eg, imperforate hymen)||Physical examination||Surgical treatment|
|Asherman’s syndrome||Endometrial destruction (eg, by vigorous curettage)||Lack of response to estrogen-progestin trial; direct visualization
of scant endometrium|
|Disorders of the ovary||Gonadal dysgenesis||Deletion of genetic material from the X chromosome||Karyotype||Remove streak gonads if Y chromosome is present in view of
high risk of germ cell cancer|
|Premature ovarian failure||Lack of viable follicles||Check gonadotropins|
|Polycystic ovary disease||Altered intraovarian hormone relationships||Clinical diagnosis in patients with chronic anovulation and androgen
excess||Decrease ovarian androgen secretion (wedge resection, oral
contraceptives); increase FSH secretion|
|Disorders of the hypothalamus or pituitary||Stress, athletic endeavor, underweight||Altered GnRH pulses||Check serum TSH, PRL, gonadotropins||Replacement if deficient; search for tumor if excessive|
Normal physiologic processes such as pregnancy and menopause.
Disorders of the uterus or the pathway of menstrual flow such
as destruction of the endometrium after curettage coupled with infection,
which can cause scarring and adhesion formation within the uterus
Disorders of the ovary such as gonadal failure resulting from
a range of chromosomal, developmental, and structural abnormalities,
autoimmune disorders, premature loss of follicles, and poorly understood
syndromes in which ovaries with follicles are resistant to gonadotropin stimulation.
Disorders of the hypothalamus or pituitary resulting in either
lack of or disordered GnRH secretion and, as a consequence, insufficient
gonadotropin secretion to maintain ovarian steroid production. The
causes of hypothalamic and pituitary dysfunction include prolactin-secreting
tumors of the pituitary gland, hypothyroidism, excessive stress
and exercise, and weight loss.
Within these categories, amenorrhea can have very diverse specific
Dysmenorrhea is pain, typically cramping in character and lower
abdominal in location, occurring in the days just before and during menstrual flow.
Dysmenorrhea can occur as a primary disorder in the absence of identifiable
pelvic disease or may be secondary to underlying pelvic disease
such as endometriosis (Table 22–6).
Table 22–6 Categories of Dysmenorrhea. |Favorite Table|Download (.pdf)
Table 22–6 Categories of Dysmenorrhea.
|Primary dysmenorrhea||Prostaglandins||Lack of organic pelvic disease|
|Endometriosis||Ectopic endometrium, including intramyometrial endometrial
tissue||Finding of endometriosis lesions on laparoscopy|
|Pelvic inflammatory disease||Infection||Positive culture|
|Anatomic lesions (imperforate hymen, intrauterine adhesions, leiomyomas,
polyps)||Congenital, inflammatory, or neoplastic||Findings on physical examination, ultrasound|
|Premenstrual syndrome (PMS)||Unknown||Association with emotional, behavioral, and other symptoms|
Vaginal bleeding is abnormal if it occurs (1) prepubertally, (2)
at the time of usual menses but is of longer than usual duration,
(3) at the time of usual menses but is heavier than usual, (4) between
menstrual periods, or (5) after menopause in the absence of pharmacologic
treatment with estrogen and progesterone (postmenopausal bleeding).
The categories of abnormal vaginal bleeding and some specific causes
are presented in Table 22–7.
Table 22–7 Causes of Abnormal Vaginal Bleeding. |Favorite Table|Download (.pdf)
Table 22–7 Causes of Abnormal Vaginal Bleeding.
|Genital lesions||Endocrine changes|
|Foreign body||Precocious puberty|
|Dysfunctional uterine bleeding||Malignant diseases|
|Estrogen breakthrough||Endometrial cancer|
|Estrogen withdrawal||Cervical cancer|
|Diseases of the genital tract||Vaginal cancer|
|Uterine leiomyoma||Ectopic pregnancy|
|Cervical polyp||Threatened abortion|
|Genital laceration||Other causes|
|Endometrial hyperplasia||Thyroid disease|
|von Willebrand’s disease|
The pathogenesis of amenorrhea depends on the level of the neuroendocrine
reproductive axis from which the disorder stems and, at each level
of the axis, whether it is due to a structural problem or to a functional
problem of hormonal control. In a previously menstruating patient
presenting with amenorrhea, it is important first to rule out pregnancy
and then to assess thyroid function (serum TSH level) and pituitary
function (serum prolactin level) before approaching the workup of amenorrhea,
compartment by compartment.
Uterine disorders—Scarring and
damage to the underlying stem cells from which the endometrium proliferates will
lead to amenorrhea. In most cases, this occurs in the setting of
endometritis after curettage (scraping of the endometrium)
either for postpartum bleeding or dysfunctional uterine bleeding.
To determine the presence of a functional endometrium, an amenorrheic
patient is given either progesterone alone or the sequential combination
of estrogen and progesterone. Renewed vaginal bleeding after cessation
of the hormonal therapy suggests that the endometrium is intact.
This response also indicates that the cause of amenorrhea lies elsewhere
(ie, is due to an endocrine defect causing lack or insufficiency
of cyclic estrogen and progesterone stimulation).
resulting from ovarian failure can be either primary or secondary
to dysfunction higher in the female neuroendocrine reproductive
axis. Primary ovarian failure occurs with a premature loss of all
follicles. This can result from genetic disorders (chromosomal aberrations),
autoimmune disorders (lymphocytic oophoritis), metabolic problems
(galactosemia) or exogenous insults such as chemotherapy, toxins,
or radiation. Secondary ovarian failure is caused by a lack of gonadotropin
stimulation of otherwise normal ovaries, resulting in failure to
produce the estrogen and progesterone needed for menstrual cycles.
a. Genetic causes—Genetic causes of
ovarian failure include Turner’s syndrome (abnormality
in or absence of an X chromosome) and mosaicism (multiple cell lines
of varying sex chromosome composition). Approximately 40% of
patients who appear to have Turner’s syndrome (short stature,
webbed neck, shield chest, and hypergonadotropic hypoestrogenic
amenorrhea) prove to be mosaics. The presence of any Y chromosome
in the karyotype of these individuals carries a high risk for gonadal
germ cell tumors and is an indication for gonadectomy. Thus, a karyotype
should be performed on any amenorrheic individual younger than 30
with high FSH and LH levels.
b. Premature ovarian failure—Premature ovarian
failure occurs when atresia of follicles is accelerated in an ovary of
a woman of reproductive age. It presents with symptoms and signs
of menopause resulting from estrogen deficiency at an inappropriately
young age. LH and FSH levels are elevated. There is a lack of estrogen
production and an absence of viable follicles. In some instances,
premature ovarian failure is just one manifestation of an autoimmune
polyglandular failure syndrome in which autoantibodies destroy a
number of different tissues, including the ovary. These patients
also may have associated hypothyroidism, adrenal insufficiency,
or pernicious anemia (Chapters 13, 20, and 21).
c. Chronic anovulation—Other patients are
found to have adequate numbers of follicles, but these fail to mature and ovulate. This condition
is known as chronic anovulation and is manifested as
amenorrhea with intermittent bleeding (caused by uncoordinated overgrowth
of the endometrium in response to stimulation by estrogen alone).
Left untreated, the high estrogen level places these women at increased
risk for endometrial carcinoma. Among the causes of chronic anovulation
is thyroid dysfunction (Table 22–8).
Both hyperthyroidism and hypothyroidism can alter ovarian function
and the metabolism of androgens and estrogens, resulting in a variety
of menstrual disorders. Another cause of chronic anovulation is
hyperprolactinemia. It has been proposed that progressively more
severe hyperprolactinemia presents first as an inadequate luteal
phase with recurrent abortion, then as anovulation with intermittent
bleeding, and finally as amenorrhea. Clinical consequences of chronic
anovulation are summarized in Table 22–9.
d. Hormonal feedback disorders—Disruption
of the coordinated cyclical interaction between the ovary and the
brain can also lead to anovulation. This occurs in patients with polycystic
ovarian syndrome (PCOS), which affects 2–5% of
reproductive age women who present with amenorrhea and hirsutism
(Table 22–10). Patients are often
obese with hyperinsulinemia with insulin resistance and dyslipidemia.
In addition, they have elevated plasma androgens, together with
elevated plasma estrogens that are predominantly estrone derived
from peripheral aromatization of adrenal androgens in the granulosa
cell by the enzyme aromatase (cytochrome P450, family 19, subfamily
A, polypeptide 1, or CYP19A1).
Table 22–8 Causes and Mechanisms of
Chronic Anovulation. |Favorite Table|Download (.pdf)
Table 22–8 Causes and Mechanisms of
|Thyroid disease||Altered estrogen clearance|
|Hyperthyroidism||Decreased androgen clearance with resulting
increased peripheral aromatization to estrogen|
|Hyperprolactinemia||Altered gonadotropin-releasing hormone (GnRH) pulses|
|Obesity||Increased peripheral aromatization of androgens to estrogens|
|Decreased steroid hormone-binding globulin, resulting in
increased free estrogen and testosterone|
|Increased insulin resistance, resulting in increased secretion
of insulin, which increases ovarian stromal production of androgens|
|Primary ovarian failure||Genetic disorders (eg, Turner’s syndrome)|
|Secondary ovarian failure||Cytotoxic drugs|
Table 22–9 Clinical Consequences of
Chronic Anovulation. |Favorite Table|Download (.pdf)
Table 22–9 Clinical Consequences of
|Menstrual dysfunction (either amenorrhea or dysfunctional
|Hirsutism and acne (androgen excess state)|
|Increased risk of endometrial cancer|
|Possible increased risk of breast cancer|
|Increased risk of cardiovascular disease|
|Increased risk of diabetes mellitus (hyperinsulinemia)|
Table 22–10 Manifestations of Polycystic
Ovary Syndrome.1 |Favorite Table|Download (.pdf)
Table 22–10 Manifestations of Polycystic
The hyperinsulinemia is believed to be a key etiologic factor. Insulin
results in decreased hepatic synthesis of steroid hormone-binding
globulin (SHBG) and insulin-like growth factor binding protein-1
(IGFBP-1) (Figure 22–12). The decreased levels
of binding proteins results in an increase in free androgens, estrogens,
and IGF-1. IGF-1 and high levels of insulin stimulate the IGF-1
receptor, leading to increased thecal androgen production in response
to LH, contributing to the hyperandrogenemic state. The high androgens
favor atresia of developing follicles and disrupt the feedback relationships
that normally result in selection of a dominant follicle for ovulation
(Figure 22–12). The resulting anovulation
is associated with amenorrhea and estrogen-induced endometrial hyperplasia
with breakthrough bleeding. The elevated estrogen levels also are implicated
in the development of endometrial cancer. Thus, events occurring
in the brain, ovary, and bloodstream of these patients work together
to constitute a vicious cycle that maintains the aberrant feedback
Pathogenesis of the various clinical manifestations of
the polycystic ovary syndrome. SHBG, steroid hormone-binding globulin;
IGFBP-1, insulin-like growth factor binding protein-1; IGF, insulin-like growth
factor; FSH, follicle-stimulating hormone; LH, luteinizing hormone.
(Redrawn, with permission, from Barnes HV. Clinical Medicine:
Selected Problems with Pathophysiologic Correlations. Year
Book Medical Publishers, 1988.)
The high levels of androgens in the bloodstream are responsible
for hirsutism. Patients with elevated androgens from totally different
causes (eg, Cushing’s disease and congenital adrenal hyperplasia)
also display amenorrhea associated with polycystic ovaries, suggesting
that the structural changes in the ovaries are secondary to the
e. Pituitary disorders—Head
trauma resulting in pituitary stalk transection with loss of hypothalamic-pituitary
communication should be considered in patients with new-onset infertility
with amenorrhea. The same is true of vascular accidents such as Sheehan’s
syndrome, in which postpartum hemorrhage causes hypotension
and consequent ischemic necrosis of the pituitary. Enlargement of
the anterior pituitary during pregnancy may predispose to ischemia
under conditions of hypotension. The pituitary approximately doubles
in size during normal pregnancy, largely as a result of hypertrophy
and hyperplasia of prolactin-secreting lactotrophs.
f. Hypothalamic disorders—Inputs from various
central pathways impinge on the mediobasal portion of the hypothalamus,
including the arcuate nucleus, from which GnRH pulses originate.
Medications and illicit drugs that affect the neurotransmitters
used in these pathways
(opioids, dopamine, and norepinephrine) can, therefore, affect GnRH
secretion as well. This underscores the importance of a taking a
detailed medication and social history in the workup of amenorrhea.
Also important is a detailed history of behavioral patterns or any
recent life changes. Psychic stress (eg, that associated with moving
to a different country) can lead to altered GnRH secretion and subsequent
amenorrhea that lasts up to 1 year. Vigorous exercise and excessive
weight loss can also lead to impaired GnRH pulsatility, accounting
for the amenorrhea seen in competitive athletes and in women with anorexianervosa.
Thus, a wide range of factors that alter pulsatile release of GnRH
can influence female reproductive physiology. Lack of menstrual
periods because of a change in one of these factors is termed hypothalamic
amenorrhea and is a common cause of infertility. Correction
of the underlying cause often leads to a return of normal cyclic
ovulation. If not, pulsatile GnRH therapy can reestablish the normal
patterns of pituitary stimulation, receptor-mediated responsiveness,
and feedback, restoring fertility.
g. Indirect influences—In
addition to factors that work directly on the GnRH-secreting neurons,
indirect influences must be considered. Primary hypothyroidism,
as well as primary or secondary hyperprolactinemia, can result in
altered GnRH pulse frequency and amplitude. The subsequent diminished
gonadotropin secretion produces a secondary ovarian failure and
amenorrhea. Examples of conditions that result in secondary hyperprolactinemia
include lactation and treatment with drugs that have dopamine-blocking
effects (eg, antipsychotic agents).
- 25. Name four kinds of stress that
can cause hypothalamic amenorrhea.
- 26. What are the consequences of untreated
Primary dysmenorrhea is due to disordered or excessive prostaglandin
production by the secretory endometrium of the uterus in the absence
of a structural lesion. Prostaglandin F2α (PGF2α)
stimulates myometrial contractions of the nonpregnant uterus, whereas
prostaglandins of the E series inhibit its contraction. It appears
that patients with severe dysmenorrhea generally have excessive
production of PGF2α rather than increased sensitivity
to this prostaglandin as a cause of excessive myometrial contraction.
Excessive contractions of the myometrium result in ischemia of uterine
muscle, which stimulates uterine pain fibers of the autonomic nervous
system. Anxiety, fear, and stress may lower the pain threshold and
thereby exaggerate the prominence of these symptoms from one patient
to another and over time in a given patient.
Among the secondary causes of dysmenorrhea is endometriosis, a
disorder in which implants of ectopic endometrial tissue respond
cyclically to estrogen and progesterone (Table
22–6). This is a common disorder affecting 10–25% of
women of reproductive age. The presenting symptoms of patients with
endometriosis can range from pain and cramping during menstruation
to adhesions with frank bowel obstruction in severe cases. Typical
locations for ectopic endometrial tissue include the pelvic portion
of the peritoneal cavity and ovaries. Establishment of endometrial
tissue in these locations is believed to occur by either or both
of two mechanisms: (1) transport of sloughed endometrial tissue by retrograde
menstruation through the uterine tubes or (2) metaplasia of undifferentiated
celomic epithelial mesenchyme in the peritoneum, perhaps under the
influence of growth factors present in retrograde menstrual efflux. Research
findings support the hypothesis of a vicious cycle involving peritoneal
inflammation with elevated cytokines in peritoneal fluid and secretion
of angiogenic factors that maintain ectopic endometrial tissue.
A characteristic feature of endometriosis is amelioration after
pregnancy and after menopause. This observation provides a therapeutic
rationale for the most common modes of medical therapy, which include
birth control pills; synthetic progestins (medroxyprogesterone acetate)
or androgens (danazol), which block the midcycle LH surge; and long-acting
GnRH analogues that down-regulate the reproductive neuroendocrine
axis. Some of these drugs may also work by downregulation of cytokine production.
It is unclear how endometriosis causes infertility, although inflammatory
cytokines have been invoked.
The pathogenesis of abnormal vaginal bleeding depends on its cause,
as outlined next.
on individual endocrine variables as described previously, the disorder
results in altered amounts and timing of genital tract flow rather than
a complete cessation of menses.
Structural lesions—Structural lesions that
alter the contour of the endometrial cavity often lead to dysfunctional uterine
bleeding. Endometrial polyps present with premenstrual or intermenstrual
spotting. Fibroids, however, more often lead to menometrorrhagia.
When these benign tumors are located within the endometrial cavity or
within the wall of the uterus, they can disrupt the regulation of
the endometrial vasculature. Therefore, very heavy prolonged or
sporadic bleeding can occur.
Malignancy—Both precancerous and cancerous
lesions of the uterus or cervix can produce abnormal vaginal bleeding.
Endometrial hyperplasia is often the consequence of excessive estrogen
stimulation or estrogen stimulation without progestin exposure.
It can progress to endometrial cancer with continued estrogen excess.
Unopposed estrogen stimulation can occur because of 1) an ovarian
disorder (eg, chronic anovulation), 2) enhanced peripheral aromatization
of adrenal androgens by cytochrome P450, family 19, subfamily A,
polypeptide 1 (CYP19A1), or 3) estrogen therapy without progestin
(eg, “natural estrogen” supplementation for perimenopausal symptoms).
Endometrial cancer is largely a peri- and postmenopausal disease;
only 5% of cases occur during the reproductive years. Endometrial
cancer spreads by direct involvement of lymphatics with distant
metastases to the lung, brain, skeleton, and abdominal organs. Patients
with endometrial cancer typically present with abnormal vaginal
bleeding. As with ovarian cancer, ascites, bowel obstruction, and
associated pleural effusions occur in widespread disease.
Dysplasia of the cervix and cervical cancer can also present with
abnormal vaginal bleeding. Carcinogens in tobacco as well as persistent
infection with certain subtypes of human papillomavirus (HPV) have
been shown to increase the risk of cervical cancer. If untreated,
cervical cancer spreads directly to the other pelvic organs; death
often occurs through hemorrhage, infection, or renal failure secondary
to ureteral obstruction. Currently, the American College of Obstetricians and
Gynecologists recommends that uninfected girls and women between
the ages of 9 and 26 years be vaccinated against HPV in order to
prevent cervical cancer.
Systemic conditions with altered coagulation—Normal blood
clotting involves both coagulation factors and platelets. Disorders
affecting the production, quality, and survival of either clotting
factors or platelets can cause abnormal vaginal bleeding (Table 22–11).
Table 22–11 Disorders of Coagulation. |Favorite Table|Download (.pdf)
Table 22–11 Disorders of Coagulation.
|Disorders resulting in thrombocytopenia|
|Suppressed platelet production|
|von Willebrand disease|
|Accelerated platelet destruction|
|Nonimmunologic (eg, prosthetic valves)|
|Viral and bacterial infections|
|Autoimmune mechanisms (eg, idiopathic thrombocytopenic
|Disorders resulting in clotting factor deficiency|
|Congenital disorders of coagulation|
|Acquired disorders of coagulation|
|Vitamin K deficiency|
|Disseminated intravascular coagulation|
- 27. What are effective medical therapies
for endometriosis, and how do they work?
- 28. What factors predispose to cervical
The clinical symptoms and signs that accompany amenorrhea depend
on its category (Table 22–5). In
genetic disorders, particularly disorders of sexual development,
various degrees of delayed puberty, such as lack of breast development
and absence of pubic hair, may accompany amenorrhea. In outflow tract
disorders (eg, imperforate hymen), pain from occult, obstructed
menstruation may occur on a cyclic basis. Generally, disorders of
the uterus and the hypothalamic-pituitary axis that result in amenorrhea
are painless. Secondary ovarian failure resulting in amenorrhea
is often preceded by symptoms referable to decreased estrogen and
progesterone production. These include hot flushes and other vasomotor
The most common complication in the nonpregnant patient with
amenorrhea is infertility. Additional complications depend on the
specific cause of lack of menstruation. Osteoporosis is a major
potential long-term complication of inadequate estrogen production.
Inadequate estrogen can also be associated with thinning of estrogen-dependent
epithelia, such as that of the vagina, resulting in atrophic vaginitis.
This symptom usually responds to topical estrogen creams. In the case
of inadequate progesterone production—typically associated
with irregular vaginal bleeding but seen also in some cases of amenorrhea—the
risk of endometrial cancer is greatly increased. Endometrial cancer
is the most common cancer of the female genital tract; 34,000 new
cases are identified annually in the United States. Risk factors
for endometrial cancer include early menarche, late menopause, nulliparity,
obesity, hypertension, and diabetes mellitus.
Dysmenorrhea may be accompanied by a variable constellation of
symptoms, including sweating, weakness and fatigue, insomnia, nausea,
vomiting, diarrhea, back pain, headache (including both migraine
and tension headaches; see Chapter 7), dizziness,
and even syncope. Prostaglandin synthesis inhibitors (nonsteroidal
anti-inflammatory agents) often alleviate many of these symptoms
if treatment is started early enough to avert the cascade of events
that occur with production of prostaglandins.
With premenstrual syndrome, dysmenorrhea is accompanied
by additional symptoms, including a sensation of bloating, weight
gain, edema of the hands and feet, breast tenderness, acne, anxiety,
aggression, mood irritability, food cravings, and change in libido.
An initial approach should be to encourage changes in lifestyle
if indicated by the history (eg, more sleep, exercise, improved
diet, and less tobacco, alcohol, and caffeine). Pharmacologic therapy
with serotonin-reuptake inhibitors (SSRIs) has proven beneficial
in addition to behavioral modification.
The symptoms and signs that accompany abnormal vaginal bleeding
vary with the cause. In children, vulvovaginitis is the most frequent
disorder, accompanied by a mucopurulent discharge that may become
bloody with mucosal erosion. Other prominent causes, including foreign
objects and tumors, can be assessed by physical examination. In
adolescents and adults, dysfunctional uterine bleeding is most common,
but other causes must be considered, including pregnancy (assessed
by serial serum β-hCG determinations and ultrasound examination),
trauma (by history and physical examination), cancer (by colposcopy
and hysteroscopy), and systemic disorders such as a hemorrhagic
diathesis (by platelet, prothrombin, and partial thromboplastin
time determinations) and thyroid disease (by serum TSH, total and
free thyroxine determinations). In postmenopausal women, one fifth
of cases of vaginal bleeding prove to be endometrial cancer.
Infertility is defined as the absence of conception after at
least 1 year of regular sexual intercourse without contraception.
In approximately 30% of cases, infertility is due to
male factors (eg, inadequate sperm count) (see Chapter 23). For female infertility, about 40% of cases are
due to ovulatory failure, about 40% are due to endometrial
or tubal disease, about 10% are due to rarer causes (eg,
thyroid disease or hyperprolactinemia), and about 10% remain
undefined after full workup (Table 22–12).
Table 22–12 Causes of Female Infertility.1 |Favorite Table|Download (.pdf)
Table 22–12 Causes of Female Infertility.1
|Cause||Patients with Infertility|
|Diminished ovarian reserve|
|Oligo-ovulation or amenorrhea|
|Tubal or pelvic pathology||40%|
|Scarring and adhesions (from pelvic inflammatory disease,
chronic infection, tubal surgery, ectopic pregnancy, or ruptured
|Pituitary disease (hyperprolactinemia)|
Infertility referable to ovarian dysfunction can result from
disorders of the hypothalamus or pituitary, resulting in inadequate
gonadotropic stimulation of the ovary; from ovarian disorders, resulting
either in inadequate secretory products or failure to ovulate; or
from both types of disorders occurring at the same time. Correction
of the underlying cause will often restore fertility. In many cases,
exogenous administration of gonadotropins will stimulate the ovaries
to produce follicular growth. The oocytes can then be released in
vivo and fertilized by intercourse or by artificial insemination.
Alternatively, the mature oocytes can be removed from the woman
to be used in in vitro fertilization (IVF), where fertilization
occurs within the laboratory and embryos are returned to the uterus.
One of the most common ovarian disorders, called diminished ovarian
reserve, is age related and can involve both the oocytes themselves
and the secretory products of the ovary. There is accelerated loss
of follicles with the approach of menopause. With follicular depletion,
FSH levels tend to rise, reflecting inadequate production of inhibin.
This could result from an inadequate number of follicles, diminished
competence of the remaining follicles, diminished steroidogenesis
by the aging ovary, or some combination of these factors. Regardless
of the specific reason, the net effect is a shortened follicular
phase and is associated with increased rates of infertility. Treatment
with clomiphene citrate, a weak estrogen antagonist, is a means
of diminishing negative feedback and increasing gonadotropin stimulation
of the ovary and restoring ovulation.
Other etiologies of ovulation dysfunction include conditions
that alter the coordination between ovary and hypothalamus, such
as PCOS and hypothalamic amenorrhea. In these scenarios, the oocytes
do not undergo the appropriate development and maturation to lead
to regular ovulation and subsequently cause infertility.
Given normal follicles and reproductive neuroendocrine axis function,
the major cause of infertility is abnormality of the endometrium
or fallopian tubes. Prior or ongoing pelvic infections, with adhesions
or inflammation, can result in failure of sperm or egg transport,
failure of implantation, or implantation in an inappropriate location
Endometriosis, presumably occurring due to the cyclic proliferation
and sloughing of ectopic endometrial tissue, results in inflammation,
scarring, and adhesion formation. New data suggest that endometriosis
may arise from a circulating endometrial stem cell population. This
condition should be suspected when infertility is associated with
severe dysmenorrhea. Surgical and medical therapies are efficacious
in the reduction of endometriosis-associated pain. The effects of endometriosis
treatment on infertility remain controversial.
of Female Infertility
Most of the less common causes of infertility can be grouped into
those disorders that affect the production of GnRH by the hypothalamus
or the hormone’s effect on the pituitary (eg, thyroid disease
- 29. What are the most common causes
of infertility in couples?
- 30. How do postcoital high-dose estrogens
work as a contraceptive?
- 31. What feature of the history suggests
a tubal or uterine cause of infertility?
Pregnancy is associated with a host of medical complications
in which clinical management requires an understanding of both the
underlying physiology of pregnancy and the pathophysiology of the
particular disorder. The syndrome of preeclampsia-eclampsia, characterized
by hypertension, proteinuria, and edema, is chosen for focus for
several reasons. First, preeclampsia-eclampsia is one of the most
common causes of maternal death in the United States and the developed
world. Second, it illustrates how pathophysiologic mechanisms in
pregnancy may be far more complex—and the clinical consequences
far more serious—than would have been expected from a simple
consideration of each of the presenting symptoms in isolation. Third, advances
have significantly altered current thinking about the pathogenesis
of this disorder.
Hypertension can develop during pregnancy as an isolated finding, pregnancy-induced
hypertension (PIH), or as a component of a dangerous
disorder, preeclampsia-eclampsia. Treatment guidelines
for PIH are different than those for essential hypertension in the
nonpregnant patient; elevated maternal blood pressure is often left
untreated unless symptomatic or if severe hypertension develops.
Because placental perfusion is dependent on a pressure difference
between the maternal and fetal circulations, decreases in maternal
blood pressure can lead to underperfusion of the placenta. This
can result in placental insufficiency and fetal distress.
The hypertension seen in preeclampsia is associated with proteinuria
and edema. This syndrome occurs in approximately 5% of
pregnancies in the United States. Eclampsia, the superimposition
of generalized tonic-clonic seizures on pregnancy-induced hypertension,
can occur as the initial presenting sign of this syndrome or during
its progression. Table 22–13 summarizes
the symptoms and signs of preeclampsia-eclampsia.
Table 22–13 Symptoms and Signs of
Preeclampsia-Eclampsia. |Favorite Table|Download (.pdf)
Table 22–13 Symptoms and Signs of
|Excessive weight gain (> 1 kg/wk)|
|Increased plasma von Willebrand factor concentration|
|Increased plasma cellular fibronectin|
|Reduced plasma antithrombin concentration|
|Reduced angiogenic activity|
|Increased packed cell volume|
|Increased serum liver enzyme levels|
|Intrauterine growth retardation|
Preeclampsia-eclampsia is thought to derive from faulty implantation,
resulting in a systemic disorder of endothelial cell activation
(see later discussion). Predisposing factors for the development
of preeclampsia include first pregnancy, obesity, preexisting
diabetes or hypertension, hydatidiform mole, malnutrition, and a
family history of preeclampsia.
The placenta of preeclamptic patients shows signs of premature
aging, including degeneration, hyaline deposition, calcification,
and congestion. The maternal decidua also shows hemorrhage and necrosis
with thrombosis of spiral arteries and diffuse infarcts.
Normally, blood vessels of the uterine wall undergo striking morphologic
changes at the site of implantation, facilitating placental perfusion.
The diameters of the spiral arteries increase and the muscular and
elastic components are lost. However, for unknown (perhaps immune-mediated)
reasons, these early angiogenic changes of implantation do not occur—or
at least not fully—in patients who will develop preeclampsia-eclampsia
later in gestation. As a result, a condition of relative placental
ischemia is established, with the release of lipid and protein factors
that damage the maternal vascular endothelium, at first within the
decidua and later systemically. Oxidative injury is believed to
work with maternal factors (eg, obesity, diabetes, diet, genes)
to cause generalized endothelial cell damage.
Endothelial activation has two important pathophysiologic consequences.
First, the balance between vasodilation and vasoconstriction is
altered, specifically by diminished production of vasodilator products
such as prostacyclin and nitric oxide, increased production of vasoconstrictive
thromboxane, endothelin and platelet-derived growth factor. As a
result, there is increased vasoconstriction of small placental bed arterioles,
with hypoperfusion and ischemia of downstream tissues and systemic
hypertension. Second, the endothelial cell barrier between platelets
and the collagen of basement membranes is breached.
As a result of the latter changes, additional events are set
in motion, including platelet aggregation, activation of the clotting cascade,
and production of vasoactive substances causing capillary leak.
This results in further tissue hypoperfusion, edema formation, and
proteinuria, the hallmarks of preeclampsia-eclampsia. Because these
processes result in further vascular endothelial damage, a vicious
circle is established.
Interesting speculation has centered on the potential of serotonin
to modulate vasodilation and angiogenic growth factors. New data
also invoke a role for agonistic autoantibodies directed against
the second extracellular loop of the angiotensin II AT1 receptor,
resulting in the vasospasm associated with preeclampsia.
Preeclampsia has a plethora of manifestations (Table
22–13). Beyond the presenting symptoms of hypertension,
edema, and proteinuria, patients also can have increased deep tendon reflexes,
or placental abruption. Hepatic periportal congestion, hemorrhage,
and necrosis can lead to elevated liver function tests and ultimate
rupture of the hepatic capsule. Severe preeclampsia also can produce
renal changes, including glomerular endothelial cell swelling, mesangial
proliferation, and marked narrowing of glomerular capillary lumens.
The renal cortex displays significant cortical ischemia that may
progress to frank necrosis and acute renal failure. Thrombocytopenia and
disseminated intravascular coagulopathy (DIC) as well as cerebral
vascular accidents also may occur (Table 22–14).
Eclampsia, or maternal seizure resulting from cerebral ischemia and
petechial hemorrhage, can occur in this setting or can appear as
the first manifestation of this disease. Preeclampsia-eclampsia
also carries risks for the fetus. Placental deterioration and insufficiency
can result in intrauterine growth restriction (IUGR) and fetal hypoxia.
Delivery of the fetus and placenta is the only definitive cure for
this syndrome, which carries a high mortality rate for mother and
child (Table 22–14).
Table 22–14 Complications of Preeclampsia-Eclampsia. |Favorite Table|Download (.pdf)
Table 22–14 Complications of Preeclampsia-Eclampsia.
|HELLP syndrome (hemolysis, elevated liver
enzymes, low platelets)|
|Disseminated intravascular coagulation (DIC)|
|Acute renal cortical necrosis|
|Acute renal tubular necrosis|
|Intrauterine fetal asphyxia and death|
- 32. What are the hallmarks of preeclampsia-eclampsia?
- 33. What are the risks to the fetus
of untreated maternal hypertension?
- 34. What are some of the maternal sequelae
(See Chapter 25 for answers)
A 24-year-old woman presents
to the clinic complaining of painful menses. She states that for
the last several years she has had cramping pain in the days preceding
her menses as well as during her menses. In addition, she notes
bloating and weight gain in the week before her menses, with swelling
of her hands and feet. She has irritability and severe mood swings
during that time such that she cries easily and for no reason seems
to become enraged at her family or boyfriend. On review of systems
she denies urinary symptoms, vaginal discharge, or GI symptoms.
She has no significant medical history. She has never been pregnant.
She has never had a sexually transmitted disease. She is sexually
active only with her long-standing boyfriend and states that they
always use condoms. She takes no medications. Her physical examination
A. What are some possible
causes of this woman’s dysmenorrhea? Which do you think
is most likely? Why?
A. Dysmenorrhea may be a primary disorder
in which no identifiable pelvic disease is present, or it may be
secondary to an underlying pelvic disease. Among the most common
causes are endometriosis, chronic pelvic infections, and adhesions
from prior infections or ectopic pregnancies. Finally, dysmenorrhea may
occur as a part of premenstrual syndrome, in which it is associated
with other symptoms, including bloating, weight gain, edema, irritability,
mood swings, and acne. This patient’s constellation of
symptoms in combination with her lack of prior medical problems
and normal physical examination makes premenstrual syndrome the
most likely diagnosis.
B. What is the pathophysiologic
mechanism responsible for her dysmenorrhea?
B. Dysmenorrhea in premenstrual syndrome
and in primary dysmenorrhea is due to disordered or excessive prostaglandin production
by the secretory endometrium of the uterus. Patients with dysmenorrhea
have excessive production of prostaglandin F2α,
which stimulates myometrial contractions of the uterus. Excessive
contractions of the myometrium cause ischemia of the uterine muscle,
thereby stimulating uterine pain fibers. Anxiety, fear, and stress
may lower the pain threshold and thereby exaggerate the prominence
of these symptoms from one patient to another and over time in a
C. How would you treat her
C. The first step in treating patients
with premenstrual syndrome is to encourage lifestyle changes such
as more sleep, exercise, improved diet, and discontinuation or decreased
use of tobacco, alcohol, and caffeine. Pharmacologic therapy with
serotonin-reuptake inhibitors (SSRIs) has proven beneficial in addition
to behavioral modification. Additionally, pain may be treated with
monthly pharmacotherapy with prostaglandin synthesis inhibitors
such as NSAIDs.
A 28-year-old woman presents
to the clinic with a complaint of infertility. She states that she
and her husband have been trying to get pregnant for approximately
1 year without success. She had menarche at age 14 years. Since
that time, she has had regular menses lasting 5 days, without significant
dysmenorrhea or abnormal bleeding. She has never been pregnant.
Medical history is notable for gonorrhea and trichomoniasis at age 18.
In addition, she has had an abnormal Pap smear consistent with human
papillomavirus at age 20 years, with normal Pap smears since that
time. She takes no medications. She has been married for 2 years
and is sexually active only with her husband. Before her marriage
she had approximately 25 sexual partners, most during her college
years. Her physical examination is unremarkable.
A. What are the most common
causes of female infertility?
A. Infertility is due to female factors
about 70% of the time. In about 40% of these cases,
it is due to ovulatory failure, as occurs in hypothalamic, pituitary,
and ovarian disorders. Another 40% are due to endometrial
or tubal disease, as occurs with pelvic infections and endometriosis.
Ten percent are due to less common causes such as those that affect
the production of GnRH by the hypothalamus or the hormone’s
effect on the pituitary (thyroid disease, hyperprolactinemia) and
those that affect ovarian feedback (hypergonadism, polycystic ovary
disease). The final 10% are of unknown cause.
B. What do you suspect is
the cause of this patient’s infertility? Why?
B. The most likely cause of this patient’s
infertility is endometrial and tubal scarring as a result of her
prior sexually transmitted diseases. Infections such as gonorrhea
and the often asymptomatic chlamydial infections can cause scarring
and adhesions. This scarring may impede sperm or egg transport and
implantation. Her history of regular menses and her normal examination
argue against the other causes of female infertility (other than
idiopathic). Finally, it is possible that the infertility results
from her husband (male factor infertility) and not the patient herself.
A 28-year-old woman presents
to her obstetrician for her regularly scheduled prenatal examination.
She is 30 weeks pregnant. She has noted some swelling of her hands
and feet in the last 2 weeks that seems to be getting progressively
worse, such that she is no longer able to wear her rings and can
only wear open-heeled shoes. She is otherwise without complaints.
She has no past medical problems. This is her first pregnancy. She has
had regular prenatal care and, thus far, with no complications.
She is taking only prenatal multivitamins. Family history is notable
for maternal hypertension and diabetes. She is married and works
as a schoolteacher. She denies alcohol, tobacco, and drug use. On
examination she appears to be well, with blood pressure of 152/95
mm Hg. Fundal height is consistent with gestational age. Fetal heart
rate is 140 beats/min. Extremities have 1+ lower
extremity edema to the knees and trace edema of the hands. Urine
dipstick reveals 3+ protein.
A. What is the likely diagnosis?
A. The most likely diagnosis is preeclampsia-eclampsia.
Although preeclampsia can be difficult to differentiate from essential
hypertension developing during pregnancy, the fact that her hypertension
developed after week 20 and was associated with edema and proteinuria
strongly suggests a diagnosis of preeclampsia.
B. What are some risk factors
for developing this condition?
B. Predisposing factors for the development
of preeclampsia include first pregnancy, multiple previous pregnancies,
preexisting diabetes or hypertension, hydatidiform mole, malnutrition,
and a family history of preeclampsia.
C. How does this condition
develop? How does it result in maternal hypertension, edema, and
C. For unclear (perhaps immune-mediated)
reasons, changes that normally occur in the blood vessels of the
uterine wall early in implantation do not occur in patients with
preeclampsia-eclampsia. A condition of relative placental ischemia
is established. Undetermined factors are released that cause damage
to vascular endothelium. This damage occurs first within the placenta
and later throughout the body. Endothelial damage alters the balance
between vasodilation and vasoconstriction, with increased vasoconstriction
of small blood vessels and resultant hypoperfusion and ischemia
of downstream tissues and systemic hypertension. The endothelial
cell barrier between platelets and the collagen of basement membranes
is breached. As a result of these changes, there is increased platelet
aggregation, activation of the clotting cascade, and production
of vasoactive substances causing capillary leak. Further tissue
hypoperfusion, edema formation, and proteinuria result. These processes
all cause further endothelial damage, thus establishing a vicious
circle. Interesting recent speculation has centered on the potential
of serotonin to modulate vasodilation or vasoconstriction, respectively,
via the 5-HT1 or 5-HT2 serotonin receptors. New
data also invoke a role for agonistic autoantibodies directed against
the second extracellular loop of the angiotensin II AT1 receptor,
resulting in the vasospasm associated with preeclampsia.
D. What are the risks to
the fetus if this condition is left untreated?
D. The risks to the fetus of preeclampsia-eclampsia
are the consequence of placental deterioration and insufficiency
and include intrauterine growth retardation and hypoxia.
E. What are the maternal
sequelae of leaving this condition untreated? What is the treatment?
E. Patients can develop multiple complications
as a result of preeclampsia-eclampsia, including malignant hypertension,
hepatic damage (periportal necrosis, congestion, and hemorrhage can
lead to elevated liver function tests and ultimately rupture of the
hepatic capsule), renal changes (glomerular endothelial cell swelling,
mesangial proliferation, marked narrowing of glomerular capillary
lumens, and cortical ischemia that may progress to frank necrosis
and acute renal failure), thrombocytopenia, disseminated intravascular
coagulopathy (DIC), and cerebrovascular accidents. Eclampsia, or
maternal seizures resulting from cerebral ischemia and petechial
hemorrhage, can occur in this setting or can appear as the first
manifestation of this disease. Delivery of the fetus is the only
definitive cure for this syndrome, which carries a high mortality
rate for mother and child.