Amenorrhea
Prof. Alaa Al-NasserObjectives
1.definition of amenorrhea
2.understand the endocrine, genetic & anatomical basis for these disorders.
3. understand clinical assessment of a patient with amenorrhea.
4. know the principles of treatment of the common causes.
Evaluation & management of patient with amenorrhea is a common practice in gynecology.
Prevalence of pathological amenorrhea ranges from 3-4% in reproductive age.
Primary(no prior menses)
Secondary(cessation of menses)
Amenorrhea is dx. In female who has not menstruating (1) by age 13 years who lacks other evidence of pubertal development.
(2) by age 15, even in the presence of other pubertal sign.
(3) for a length of time equivalent to a total of three previous cycle intervals or 6 months.
It is reasonable to initiate an evaluation despite the absence of these strict criteria. Ex. Stigmata of Turner syndrome, obvious virilization or history uterine curettage.
A differential dx. For amenorrhea can be developed based on requirements for normal menses which requires precise reproductive hormones.
Classification system
Numerous classification systems for diagnosis of amenorrhea have been developed ( anatomic versus hormonal),(inherited versus acquired disorders)
Categories of amenorrhea based on gonadotropin and estrogen levels.
Classification scheme for amenorrhea
Anatomic
Inherited (mullerian agenesis, vaginal septum, cervical atresia, imperforate hymen, labial fusion)
These are frequent cause of amenorrhea in adolescents &pelvic anatomy is abnormal in 15%. Out flow obstruction labial agglutination or fusion or fusion is associated with disorder of sexual development particularly of pseudohermaphradite due to excess of androgen exposure in female fetus in utero(androgen from fetus CAH or maternal luteoma in pregnancy).
Imporforated hymen, transverse vaginal septum, or isolated atresia of vagina and cervix (46 XX, female 2ndry sex k.k, normal ovarian function, amount of uterine bleeding is normal but typical path to egress is obstructed or absent, have breast tenderness, food graving &mood changes due to progesterone level, cyclical abdominal pain or palpable abdominal mass ,retrograde menstruation lead to endometriosis which lead to chronic pain and infertility.
Mullerian defects
During embryonic development mullerian ducts give rise to upper vagina, cervix, uterine corpus and F.T, agenesis may be partial or complete. Ameanorrhea may be due to out flow obstruction or lack of endometrium in case of lack endometrium in mullerian agenesis( Mayer- Rokitansky syndrome) no any mullerian structure only vaginal dimple. It may be confused with androgen insensitivity in this condition patient has 46XY , normal function testis, but the body cannot respond to testosterone due to androgen receptor mutation.
Acquired
Amenorrhea due to stenosis of cervix (conization, elecrosurgury or cryosurgery used to treat cervical dysplasia).
Extensive intra uterine scarring =synechiae(hypomenorrhea or pregnancy loss)
It may follow vigorous curettage usually in associated with PPH, miscairage, therapeutic abortion complicate by infection, metroplasty, myomectomy, C/S , infection with IUCD, tuberculus endometritis. If those patient develop pregnancy risk of uterine repture &placenta accrete.
Endocrine disorder
Hypergonadotrophic hypogonadism
It refer to any process in which ovarian function decrease or absent (hypogonadism)due to lack of negative feedback,FSH,LH increased, primary dysfunction of ovary rather than centrally(POF) = loss of oocyte and surrounding cells prior to age of 40. Dx FSH , LH above 40mIU/ml tow time one month apart. Incidence 1-1000 in less than 30 and 1-100 in less than 40 y.
Heritable disorders
Chromosomal defects: gonadal dysgenesis is the most common cause of POF, oocyte undergo accelerated atresia in early fetal ovary which replace by fibrous streak.
May be normal or abnormal karyotype(45,X turner), chromosomal mosaisicism(45,X/46,XX).
Normal karyotype gonadal dysgenesis(46XX or 46, XY).
Specific gene defects mutation in CYP17 result in decrease 17 a-hydroxylase prevent cortisol, androgen, estrogen(sexual infantilism)
Mutation in LH&FSH, Galactosemia .
Acquired abnormalities
Autoimmune disease POF may be one of poyglandular failure with hypothyroidism, adrenal insuffeciency, SLE, myasthenia gravis, idiopathic thrombocytopenic purpura, R.A, vitiligo&autoimmune hemolytic anaemia.
Iatrogenic POF =surgical excision, chemotherapy, radiation, environmental toxins eg. Smoking, heavy metals, solvents, pesticides& industrial chemicals.
Hypogonadotropic hypoganadism
Primary abnormolaties in the hypothalamic pitutary axis(FSH, LH very low or undetectable)
Absence of menses for more than three cycles or six months in women who previously had menses
ETIOLOGY
Pregnancy — Pregnancy is the most common cause of secondary amenorrhea. It may occur even in women who claim that they have not been sexually active or are positive that intercourse occurred at a "safe" time. It is also important to note that apparent menstrual bleeding does not exclude pregnancy, since a substantial number of pregnancies are associated with some early first trimester bleeding.
Hypothalamic dysfunction — one of the most common types of secondary amenorrhea is functional hypothalamic amenorrhea, which by definition excludes pathologic disease. Although rare, infiltrative diseases of the hypothalamus can cause secondary amenorrhea.
Congenital GnRH deficiency
Functional hypothalamic amenorrhea — Functional hypothalamic amenorrhea, or functional hypothalamic GnRH deficiency, is a disorder that, by definition, excludes pathologic disease. It is characterized by a decrease in hypothalamic gonadotropin-releasing hormone (GnRH) secretion
Multiple factors may contribute to the pathogenesis of functional hypothalamic amenorrhea, including eating disorders such as anorexia nervosa, exercise, and stress. However, in a few women with functional hypothalamic amenorrhea no obvious precipitating factor is evident.
Hypothalamic amenorrhea can be caused by nutritional deficiencies that are not associated with weigh loss or strenuous exercise, the women with amenorrhea severely restricted their fat consumption and had lower body fat mass.
Amenorrhea due to nutritional deficiencies is celiac disease. Emotional stress and stress induced by illness (eg, myocardial infarction, severe burns)
Women with hypothalamic amenorrhea have lower serum leptin concentration.
Genetic basis, there is marked interpatient variability in the degree of weight loss or exercise required to induce amenorrhea.
Infiltrative lesions
Systemic illness — Systemic illness may be associated with menstrual cycle disorders when it is severe enough to result in a decrease in hypothalamic GnRH secretion, and/or when it is associated with nutritional deficiencies.
Pseudocyesis is a somatoform disorder characterized by a false, but non-delusional, belief in being pregnant. Abdominal enlargement and menstrual irregularities Sensation of fetal movement gastrointestinal symptoms Breast changes abdominal pain Urinary frequency other signs and symptoms associated with pregnancy are common in women with pseudocyesis. Symptoms generally last from a few weeks to nine months or longer. Recurrences may occur. Prognosis is dependent, to a large extent, on resolution of the specific psychological and/or interpersonal factors that have been involved in the development of pseudocyesis in the patient. Treatment goals include disappearance of physical signs and symptoms of pregnancy, improved social and occupational functioning, and reduced risk of recurrence.
Pituitary disease — A lactotroph adenoma (prolactin-secreting pituitary tumor, prolactinoma).
Hyperprolactinemia — Hyperprolactinemia has a similar presentation to functional hypothalamic amenorrhea except for the occasional additional finding of galactorrhea in some women.
Sheehan's syndrome, radiation, infarction, and infiltrative lesions of the pituitary gland, such as hemochromatosis, and lymphocytic hypophysitis, are all uncommon causes of gonadotropin deficiency
Pituitary infarction (Sheehan's syndrome)
Infarction of the pituitary gland after postpartum hemorrhage has long been recognized as a cause of hypopituitarism.A history of postpartum hemorrhage so severe as to cause hypotension and require transfusion of multiple units of blood. When the hypopituitarism is severe, development of lethargy, anorexia, weight loss, and inability to lactate during the first days or weeks after delivery.
When the hypopituitarism is less severe, failure of postpartum lactation and failure to resume menses in the weeks and months after delivery and loss of sexual hair, as well as milder degrees of fatigue, anorexia.
Ovarian disorders — the major ovarian causes of secondary amenorrhea are hyperandrogenism, from internal or external sources, and ovarian failure due to normal or early menopause. I
Polycystic ovary
Premature ovarian failure (Primary ovarian insufficiency) — Premature ovarian failure occurs when the supply of oocytes and surrounding follicles is depleted.
Depletion of oocytes before age 40 years is called premature menopause or premature ovarian failure, as this disorder is typically characterized by a waxing and waning clinical course. As a result, intermittent follicular development, estradiol production, menstrual bleeding, LH surges, and ovulation can occur between months of hypoestrogenemia causes: idiopathic, genetic female with fragile x syndrome, autoimmune, radiation, chemotherapy.
Uterine disorders — Asherman's syndrome is uterine cause of secondary amenorrhea. This syndrome results from acquired scarring of the endometrial lining, usually secondary to postpartum hemorrhage or endometrial infection followed by instrumentation such as a dilatation and curettage. This abnormality prevents the normal build-up and shedding of endometrial cells, leading to very light or absent menses.
The diagnosis is suggested by the absence of a normal uterine stripe on pelvic ultrasound and may be confirmed by the absence of withdrawal bleeding after administration of estrogen and then progestin for several weeks. The presence of Asherman syndrome can be verified by hysteroscopic evaluation of the endometrium.
DIAGNOSIS — Once pregnancy and Asherman's syndrome have been excluded, all of the remaining causes of amenorrhea are associated with anovulation due to hypothalamic, pituitary, or ovarian disorders.
Step 1: Rule out pregnancy — A pregnancy test is recommended as a first step in evaluating any woman with secondary amenorrhea.
Step 2: History —
1. The woman should be questioned about any past medical history, risk factors, or symptoms that might suggest any of the major causes of secondary amenorrhea.
2. Has there been recent stress; change in weight, diet or exercise habits; or illness that might result in hypothalamic amenorrhea.
3. Is the woman taking any drugs that might cause or be associated with amenorrhea?The drug may be taken for a systemic illness that itself can cause hypothalamic amenorrhea. Recent initiation or discontinuation of an oral contraceptive can be associated with several months of amenorrhea, as can androgenic drugs like danazol or high-dose progestin. Other drugs cause amenorrhea by increasing serum prolactin concentrations, including metoclopramide and antipsychotic drugs.
4. Has the woman developed new acne, hirsutism, or deepening of the voice?
5. Are there symptoms of other hypothalamic-pituitary disease, including headaches, visual field defects, fatigue, or polyuria and polydipsia?
6. Are there any symptoms of estrogen deficiency, including hot flashes, vaginal dryness, poor sleep, or decreased libido? These symptoms may be prominent in the early stages of ovarian insufficiency. In contrast, women with hypothalamic amenorrhea do not usually have these symptoms despite the presence of similarly low serum estrogen concentrations.
7. Is there galactorrhea (suggestive of hyperprolactinemia), or hirsutism, acne, and a history of irregular mense.
8. Is there a history of obstetrical catastrophe, severe bleeding, dilatation and curettage, or endometritis or other infection.
Step 3: Physical examination
The examination in women with secondary amenorrhea should include measurements of height and weight. A body mass index greater than 30 kg/m2 is observed in approximately 50 percent of women with PCOS. Women with a BMI less than 18.5 kg/m2 may have functional hypothalamic amenorrhea due to an eating disorder, strenuous exercise, or asystemic illness associated with weight loss.
The patient should be examined for hirsutism, acne, striae, acanthosis nigricans, vitiligo, and easy bruisability. Breasts should be examined for evidence of galactorrhea, and vulvovaginal exam should look for signs of estrogen deficiency.
Step 4: Basic laboratory testing
measurement of serum hCG to rule out pregnancy. measurements of serum prolactin, FSH, and TSH to test for hyperprolactinemia, ovarian failure, and thyroid disease.
Step 5: Follow-up testing — further evaluation depends upon the results of the initial evaluation
Normal serum prolactin and FSH concentrations with history of uterine instrumentation preceding amenorrhea — Evaluation for Asherman's syndrome (intrauterine adhesions) should be performed. Many clinicians start with a progestin challenge (medroxyprogesterone acetate 10 mg for 10 days). If withdrawal bleeding occurs, an outflow tract disorder has been ruled out.
If bleeding does not occur, estrogen and progestin may be administered. The endometrium may be primed with oral conjugated estrogens 0.625 mg/day or its equivalent (oral estradiol 1 mg/day, transdermal estradiol 0.05 mg) for 35 days. A progestin is then added from days 26 to 35 (typically medroxyprogesterone 10 mg/day). Failure to bleed upon cessation of this therapy strongly suggests endometrial scarring. In this situation, a hysterosalpingogram or direct visualization of the endometrial cavity with a hysteroscope can confirm the diagnosis of intrauterine adhesions.
A high serum androgen value may solidify the diagnosis of PCOS or may raise the question of an androgen-secreting tumor of the ovary or adrenal gland. Tumors are typically associated with the rapid onset of virilizing symptoms and, in some cases, with glucocorticoid excess. Most clinicians initiate evaluation for a tumor if the serum concentration of testosterone is greater than 150 to 200 ng/mL (5.2 to 6.9 nmol/L) or that of DHEA-S is greater than 700 mcg/dL (13.6 µmol/L).'
TREATMENT — Treatment of women with secondary amenorrhea should be directed at correcting the underlying pathology, if possible; helping the woman to achieve fertility, if desired; and medical treatment to prevent complications of the disease process (eg, estrogen replacement to prevent osteoporosis).
Hypothalamic amenorrhea
For many athletic women, simply explaining the need for adequate caloric intake to match energy expenditure results in increased caloric intake or reduced exercise, followed by resumption of menses. Cognitive behavioral therapy may be effective for restoring ovulatory cycles in some women with functional hypothalamic amenorrhea.
Nonathletic women who are underweight or who appear to have nutritional deficiencies should have nutritional counseling and can be referred to a multidisciplinary team specializing in the assessment and treatment of individuals with eating disorders.
Hyperprolactinemia — A dopamine agonist will correct hyperprolactinemia in most women.
Premature ovarian failure (Primary ovarian insufficiency) — Women with primary ovarian insufficiency should receive postmenopausal hormone therapy for prevention of bone loss. This can be either an oral contraceptive (if the patient is having intermittent ovarian function and does not wish to become pregnant or replacement doses of estrogen and progestin/PCOS — Treatment of hyperandrogenism is directed toward achieving the woman's goal (eg, relief of hirsutism, resumption of menses, fertility) and preventing the long-term consequences of PCOS (eg, endometrial hyperplasia, obesity, and metabolic defects.
Intrauterine adhesions — Therapy of Asherman’s syndrome consists of hysteroscopic lysis of adhesions followed by long-term estrogen administration to stimulate regrowth of endometrial tissue.