Secondary Amenorrhea
The etiologies of primary and secondary amenorrhea often overlap. Those
more commonly associated with primary amenorrhea are discussed in Chapter 30.
Most secondary amenorrhea results from anovulation. The most common reason is pregnancy;
this etiology should be evaluated before considering any other cause. An
algorithm for evaluating secondary amenorrhea is shown in Fig. 31.1.
Polycystic ovary syndrome (PCOS) is the most common cause of chronic anovulatory amenorrhea. It is a
disorder characterized by amenorrhea or oligomenorrhea, physical signs of
hyperandrogenism (hirsutism, acne) and the presence of enlarged polycystic
ovaries. PCOS pathophysiology can be linked to the combination of: (i) exaggerated
pulsatile gonadotropin-releasing hormone (GnRH) secretion, causing elevated
circulating luteinizing hormone (LH) and an increased LH : FSH
(follicle-stimulating hormone) ratio; and (ii) defects in insulin signaling for
glucose transport and lipolysis, causing insulin resistance (Fig. 31.2).
The mechanism for the exaggerated
GnRH pulse frequency and amplitude is unknown, but its appearance at puberty
suggests an intrinsic, primary pathogenic defect. Pituitary gonadotrophs are
exquisitely sensitive to the frequency and amplitude of GnRH pulses and the
pattern present in patients with PCOS causes a relative increase in the
secretion of LH with respect to FSH. Ovarian theca cells respond to LH by
increasing cholesterol conversion to androgens (Chapter 2). Conversion of these
androgens to estrogen in the ovary is reduced by a decrease in aromatase
activity that accompanies the relative FSH deficiency. Hyperandrogenism, in
turn, causes local follicular arrest and anovulation and systemic stimulation
of sex steroid-responsive hair follicles, resulting in hirsutism and acne. The
androgen-producing theca cells in the ovaries of patients with PCOS become
hyperplastic and are surrounded by an increased number of developmentally
arrested primary and secondary follicles, which can be documented ultrasonographically
as enlarged ovaries encircled by a “string of pearls.”
Insulin abnormalities are as
important in PCOS as are those in the GnRH pulse generator. In fact, therapy
with insulin sensitizers can correct both metabolic and hormonal alterations.
In untreated patients, cellular defects in glucose transport result in
transient hyperglycemia and reactive hyperinsulinemia. Insulin synergizes with
LH to stimulate androgen production by theca cells and inhibits the hepatic
production of sex hormonebinding globulin (SHBG), thereby increasing
circulating free androgen. The cellular lipolytic defect in women with PCOS
results from a reduction in β-adrenoceptor density on adipocytes and causes
increased fat storage and obesity. Obesity, present in over half of women with
PCOS, amplifies the abnormalities of insulin resistance and hyperinsulinemia.
The somatotropic (growth) axis
has also been implicated in PCOS pathogenesis. Growth hormone (GH) and its
peripheral mediators, insulin-like growth factors (IGFs), their binding
proteins (IGFBPs) and their receptors enhance steroidogenesis by ovarian theca
and granulosa cells. Nonobese patients with PCOS have exaggerated GH pulse
amplitudes, similar to their exaggerated GnRH pulses. In contrast, obese women
with PCOS have hyperinsulinemia but blunted GH secretion. Because insulin
interacts with the IGF system at multiple levels and can bind to the IGF-1
receptor, hyperinsulinemia mimics GH excess. In either case, there will be
increased somatotropic activity and excessive androgen production in the ovary.
At least 50% of women with PCOS
also show functional adrenal hyperandrogenism, making differentiation of PCOS
from late-onset congenital adrenal hyperplasia (CAH) difficult. The exact
nature of the adrenal dysfunction in PCOS is unclear, but evidence points to an increase in P450c17 activities in the zona
reticularis of the adrenal cortex. LH, insulin and IGF-1 stimulate this enzyme
in the ovary to produce androgens. Patients with PCOS with functional adrenal
hyperandrogenism have exaggerated adrenal androgen production in response to
adrenocorticotropic hormone (ACTH) stimulation. Excessive adrenal androgen
production during adrenarche may trigger the onset of PCOS in these women by
increasing serum androstenedione that is converted extragonadally to the weak
estrogen estrone. Inappropriate estrone production, in turn, may produce a
premature and pathologic trophic effect on the reproductive axis, causing PCOS
at puberty.
Treatment of PCOS aims to reduce
insulin resistance, to establish ovulation when fertility is desired, and to
prevent prolonged unop- posed estrogen activity during anovulation and its
associated risk for endometrial hyperplasia and cancer. Antiandrogens may be
required to treat acne and hirsutism caused by hyperandrogenism.
All functional hypothalamic
disorders are associated with decreased GnRH pulse frequency and amplitude.
CNS input to the GnRH pulse generator can be disrupted by the psychogenic
starvation of anorexia nervosa, by strenuous exercise and by stress.
Infiltrative diseases of the hypothalamus such as lymphoma and histiocytosis,
while rare, can also disrupt GnRH secretion.
Amenorrhea resulting from excessive
prolactin secretion can arise from multiple abnormalities, including
prolactin secreting microadenomas and macroadenomas, hypothyroidism and use of
a wide variety of medications (Chapter 32).
Premature ovarian failure (POF), the cessation of menses before age 40 in the absence of genetic
abnormalities, accounts for 10% of the cases of secondary amenorrhea. Women
with POF typically exhibit amenorrhea, elevated gonadotropin levels and
decreased circulating estrogens. Many will have hot flashes. In most cases, the
exact cause for ovarian failure will not be found. Some cases of POF are associated
with autoimmune diseases such as Hashimoto thyroiditis, Addison disease,
hypoparathyroidism and myasthenia gravis, or may be part of a polyendocrine
syndrome. Antibodies to gonadotropins and gonadotropin receptors have been
found in some patients. Others lack antibodies, but carry genetic mutations in
LH or FSH receptors. Occasionally, ovarian failure is temporary and pregnancies
have followed an apparent cessation of ovarian function.
Intrauterine synechiae or
adhesions occlude the uterine cavity in Asherman syndrome. Because the condition may develop after an intrauterine infection or postpartum
curettage for heavy bleeding, it is thought that these procedures can
inappropriately remove deep endometrial layers and destroy the basal crypts and
glands necessary for endometrial regeneration. The scarring associated with
Asherman syndrome can totally obliterate the uterine cavity, although milder
degrees of scarring can also cause amenorrhea. Direct injury and local
paracrine dysfunction may both be involved.
Hypothyroidism is
associated with menstrual irregularities and amenorrhea. Thyroxine can increase
estrogen and progesterone secretion by cultured human granulosa cells and
thyroid hormone deficiency may adversely alter ovarian steroidogenesis. Also,
the increased hypothalamic secretion of thyrotropin-releasing factor (TRF) accompanying
primary hypothyroidism will stimulate prolactin secretion. The resulting
hyperprolactinemia inhibits pulsatile GnRH secretion and causes menstrual
irregularities (Chapter 32).
CAH, Cushing syndrome and obesity
all are associated with excess androgen production. Although adrenal
androgens (DHEA and DHEA-S; Chapter 2) are relatively weak, their presence in
pathologic amounts can lead to significant androgenic effects. Most effects
occur after conversion to more potent androgens and estrogens in peripheral
cells such as adipocytes. In women, the resultant noncyclic,
gonadotropin-independent sex steroid secretion interferes with normal cyclic
secretion of FSH and LH by the pituitary and causes oligo or anovulation.
In empty sella syndrome,
the bony structure surrounding the pituitary gland is flattened and appears
enlarged and empty. Some patients with an apparently empty sella have headaches
and no endocrine dysfunction. Others have single or multiple endocrinopathies
including gonadotropin deficiencies and hyperprolactinemia. The cause of
empty sella syndrome is unknown.
The pituitary gland is
particularly vulnerable to hypotensive injury during pregnancy. Pituitary
infarction associated with postpartum hemorrhage and shock is called Sheehan
syndrome. In Sheehan’s original description, patients presented with
panhypopituitarism. Such severe forms of Sheehan syndrome are rarely
encountered in modern obstetric practice, but partial forms occasionally are.
The severity of the injury determines the specific pituitary functions affected
and loss occurs in a fairly predictable order. Most vulnerable is GH secretion.
More severe cases will impair, in decreasing order of frequency, prolactin,
thyroid-stimulating hormone and ACTH secretion.
