Secondary Amenorrhea - pediagenosis
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Monday, November 5, 2018

Secondary Amenorrhea

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.

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