Secondary amenorrhea

A 30-year-old woman presents with a history of no menses since she stopped taking oral contraceptives 6 months ago in order to conceive. She had undergone puberty that was normal in both timing and development, with menarche at 12 years of age. At 18 years of age, she started taking oral contraceptives for irregular menses. She reports stress at work. Her weight is 59 kg, and her height 1.66 m; her body-mass index (the weight in kilograms divided by the square of the height in meters) is 21.3. There is no galactorrhea, hirsutism, or acne. The pelvic examination is normal, a pregnancy test is negative, the prolactin level is normal, and the follicle-stimulating hormone (FSH) level is in the menopausal range. How should she be evaluated and treated?
THE CLINICAL PROBLEM
The ovary is unique in the endocrine system in that an entirely new secretory structure is developed within it each month — the graafian follicle, which arises from a microscopic primordial follicle. Menopause, defined as the permanent cessation of menses, results from the depletion of potentially functional primordial follicles. The mean (±SD) age at the time of natural menopause is 50±4 years.1 Menopause before the age of 40 years is considered to be premature.
Primary ovarian insufficiency is the preferred term for the condition that was previously referred to as premature menopause or premature ovarian failure; other terms used for this condition include primary ovarian failure and hypergonadotropic hypogonadism, as well as the misnomer, gonadal dysgenesis.2,3 The condition is considered to be present when a woman who is less than 40 years old has had amenorrhea for 4 months or more, with two serum FSH levels (obtained at least 1 month apart) in the menopausal range.4,5 The condition differs from menopause in that there is varying and unpredictable ovarian function in approximately 50% of cases, and about 5 to 10% of women conceive and deliver a child after they have received the diagnosis.4,6-9 Thus, the term “primary ovarian insufficiency,” as originally suggested by Albright, meets the need to describe a continuum of impaired ovarian function rather than a dichotomous state.2,3 This term may also be less stigmatizing than the terms that were used previously.

In 90% of the cases of primary ovarian insufficiency, the cause remains a mystery. Spontaneous 46,XX primary ovarian insufficiency can occasionally occur as part of a syndrome

In addition, several single genes (e.g., bone morphogenetic protein 15 [BMP15], diaphanous homolog 2 [DIAPH2], and inhibin alpha subunit [INHA]) have been associated with nonsyndromic primary ovarian insufficiency, but their clinical relevance is not clear. Structural abnormalities in the X chromosome apart from specific gene mutations may also be a cause.

Primary ovarian insufficiency occurs through two major mechanisms: follicle dysfunction and follicle depletion.5 Follicle dysfunction indicates that follicles remain in the ovary, but a pathologic process prevents their normal function (e.g., as a result of an FSH-receptor mutation).10 Follicle depletion indicates that no primordial follicles remain in the ovary. This condition may be due to the failure of an adequate initial pool of primordial follicles to be established in utero, an accelerated expenditure of follicles, or autoimmune or toxic destruction of follicles

This review focuses on spontaneous 46,XX primary ovarian insufficiency, which affects approximately 1 in 100 women by the time they are 40 years of age.13

STRATEGIES AND EVIDENCE
Evaluation
There is no menstrual history that is characteristic of the development of spontaneous 46,XX primary ovarian insufficiency.5 In most cases, the condition develops after a normal puberty and established regular menses, although primary amenorrhea may be the presenting feature in about 10% of cases.4 Occasionally, menses stop abruptly. In some women, menses fail to resume after a pregnancy or after they have stopped taking hormonal contraceptives. Most commonly, there is a prodrome of oligomenorrhea, polymenorrhea, or dysfunctional uterine bleeding.

Once pregnancy has been ruled out, clinicians evaluating women with secondary amenorrhea should address several questions: Is this condition the earliest manifestation of a decline in general health, such as uncontrolled diabetes mellitus, or of an underlying condition, such as celiac disease?14,15 Is it related to excessive exercise, inadequate caloric intake, or emotional stress? Has the woman undergone prior radiation therapy or chemotherapy? Is there galactorrhea (suggestive of hyperprolactinemia) or are there signs of androgen excess? Although the list of potential causes of secondary amenorrhea is long, the majority of cases are accounted for by four conditions: the polycystic ovary syndrome, hypothalamic amenorrhea, hyperprolactinemia, and primary ovarian insufficiency.14 It is inappropriate to attribute amenorrhea to stress without further evaluation.

Diagnostic criteria have not been established by any professional organization. A commonly used definition requires that there be at least 4 months of amenorrhea.4,16 However, because approximately 50% of women with primary ovarian insufficiency have intermittent ovarian function leading to intermittent and unpredictable menses, rather than complete amenorrhea, a more practical definition is 4 months or more of “disordered” menses (amenorrhea, oligomenorrhea, polymenorrhea, or metrorrhagia) in association with menopausal FSH levels.
Symptoms of estrogen deficiency develop in many, but not all, patients. These symptoms include vasomotor symptoms (hot flashes and night sweats), sleep disturbance, and dyspareunia related to vaginal dryness. However, not all patients have profound estrogen deficiency, and a vaginal examination often shows effects suggesting normal estrogen levels.

Although most cases of primary ovarian insufficiency occur sporadically, there is a positive family history, with an affected first-degree relative, in approximately 10 to 15% of cases.17 Thus, patients should be queried about family history as well as about other autoimmune disorders (including hypothyroidism, adrenal insufficiency, and hypoparathyroidism) that might relate to an autoimmune polyglandular syndrome. The condition may also be associated with the dry-eye syndrome, myasthenia gravis, rheumatoid arthritis, or systemic lupus erythematosus.18,19 A family history of the fragile X syndrome, intellectual disability, dementia, tremor or ataxia, or symptoms similar to those associated with Parkinson's disease might point to a premutation in the fragile X mental retardation 1 (FMR1) gene.20
The physical examination may reveal evidence of an associated disorder such as hyperpigmentation or vitiligo (which is associated with autoimmune adrenal insufficiency), thyroid enlargement, or stigmata indicative of Turner's syndrome, such as short stature, webbed neck, and high, arched palate.

After pregnancy is ruled out, the initial evaluation of amenorrhea should include, at a minimum, the measurement of serum prolactin, FSH, and thyrotropin levels.14 In cases of amenorrhea caused by stress (i.e., hypothalamic amenorrhea), the serum FSH level is in the low or normal range. If the FSH level is in the menopausal range, as defined by the reporting laboratory, the test should be repeated in 1 month along with a serum estradiol measurement. A progestin-withdrawal test (in which a progestin is administered and then withdrawn in order to determine whether vaginal bleeding ensues after its withdrawal) was previously used as a diagnostic test of ovarian function, but it is not currently recommended. Nearly 50% of women with primary ovarian insufficiency have withdrawal bleeding in response to the test, despite the presence of menopausal-level gonadotropins, and in the case of these women, relying on this bioassay would delay the diagnosis.4
In cases of primary ovarian insufficiency that are not associated with a syndrome, the laboratory tests that are recommended to determine the cause include a karyotype analysis and testing for an FMR1 premutation and for adrenal antibodies (with the use of indirect immunofluorescence or 21-hydroxylase [CYP21] immunoprecipitation); pelvic ultrasonography should also be performed. Approximately 2% of women with isolated spontaneous 46,XX primary ovarian insufficiency and 14% with familial spontaneous 46,XX primary ovarian insufficiency have an FMR1 premutation, which confers a risk of having a child with fragile X syndrome.20 The results of adrenal antibody testing are positive in approximately 4% of women with primary ovarian insufficiency. These women have steroidogenic cell autoimmunity, and lymphocytic autoimmune oophoritis is the mechanism of the ovarian insufficiency (Figure 1FIGURE 1
Transvaginal Ultrasound Scan from a Patient with Spontaneous 46,XX Primary Ovarian Insufficiency Who Had Follicle Dysfunction Due to Autoimmune Oophoritis.
). Ovarian antibodies lack specificity, and testing for them is not warranted. 21 Pelvic ultrasonography identifies cases involving enlarged, multifollicular ovaries, which may undergo torsion, such as in isolated 17,20-lyase deficiency or autoimmune oophoritis

An ovarian biopsy does not provide information that is helpful in the management of primary ovarian insufficiency and is therefore not indicated; pregnancy may occur even after examination of a biopsy specimen has shown that follicles are absent.6

Management
The diagnosis of primary ovarian insufficiency affects a woman's physical and emotional well-being, and the management of the condition should address both. Other associated endocrine deficiencies, as well as anxiety, depression, or both, may develop. The presence of an abnormal karyotype, an iatrogenic cause, or a premutation in the FMR1 gene has additional health implications

Emotional Health
Unexpected infertility is a life-altering diagnosis for many women.22 Shyness and social anxiety, impaired self-esteem, and a perceived low level of social support are more frequent among women with spontaneous 46,XX primary ovarian insufficiency than among women who do not have this condition.23,24 Many women report experiencing severe emotional distress25 and want guidance on how to cope with the emotional sequelae, but few ask for it directly. It is best to schedule a return office visit to inform women of this diagnosis; patients should be encouraged to identify sources of emotional support.24
Hormone-Replacement Therapy
Early menopause has been associated with an increased incidence of fractures26 and increased total mortality and mortality due to ischemic heart disease.27-29 In a study of women who were part of the Women's Health Initiative, combined hormone-replacement therapy (estrogen with progestin) increased the risk of cardiovascular events; however, it is invalid to apply the results of this study, which involved menopausal women who were, on average, 63 years of age,30 to young women with primary ovarian insufficiency. (Menopause is a physiologic condition, whereas primary ovarian insufficiency is a pathologic condition in which women have low serum estradiol levels as compared with other women of similar age.) Although data from randomized, controlled trials are lacking, most experts agree that physiologic estrogen and progestin replacement is reasonable in the case of young women with primary ovarian insufficiency and should be continued until they reach the age when menopause usually occurs.3
The average serum estradiol level during the menstrual cycle in women with a normal menstrual history is approximately 100 pg per milliliter.31 Although no studies have directly compared various hormonal therapies for women with primary ovarian insufficiency, a dose of 100 μg of estradiol per day, administered by transdermal patch, achieves average serum estradiol levels in this range and effectively treats symptoms. Transdermal estradiol has little effect on hemostatic factors, and in case–control studies, it has been associated with a lower risk of venous thromboembolism than has oral estrogen.32-34– Evidence supports the use of cyclic medroxyprogesterone acetate at a dose of 10 mg per day for 12 days each month as the preferred progestin. This regimen fully induces secretory endometrium and provides protection against endometrial cancer. 35,36 Data regarding the effects on the endometrium of oral micronized progesterone when it is given in conjunction with a full replacement dose of estrogen are not available.37 Patients should keep a menstrual calendar and take a pregnancy test if a menstrual period is late. Pregnancy may occur while a woman is taking estrogen and progestin therapy, and the therapy should be stopped if the pregnancy test is found to be positive. Oral contraceptives provide more steroid hormone than is needed for physiologic replacement and are therefore not recommended as first-line management.

Maintaining Bone Health
Women with primary ovarian insufficiency have reduced bone mineral density as compared with controls.38 Thus, bone mineral density should be measured, and women should be educated regarding strategies to maintain bone health. No data are available specifically for these women with regard to the recommended daily intake of calcium and of vitamin D and the recommended frequency and intensity of weight-bearing exercise, but it seems reasonable to follow the guidelines developed for perimenopausal and postmenopausal women by the North American Menopause Society: intake of 1200 mg of elemental calcium per day and maintenance of adequate vitamin D status, which is defined as a serum 25-hydroxyvitamin D level of 30 ng per milliliter (75 nmol per liter) or higher. 39 Vitamin D deficiency is common, and it has been recommended that adults with inadequate exposure to the sun take at least 800 to 1000 IU of vitamin D3 per day.40 Women should be encouraged to engage in a variety of exercises, such as jogging, walking, and stair climbing, along with resistance exercises.41 Bisphosphonates are not advised if pregnancy is possible, since these agents have long skeletal half-lives and the effects on the fetus are uncertain.42

Associated Disorders
There is a 50% risk of the development of adrenal insufficiency in women with adrenal autoimmunity.43 Patients with positive tests for adrenal antibodies should be evaluated annually with the use of a corticotropin stimulation test. Longitudinal data are lacking to guide the optimal follow-up for patients with negative tests for adrenal antibodies at the initial examination. Theoretically, one would expect adrenal-cell antibodies to be present when the ovarian insufficiency develops if the mechanism is steroidogenic cell autoimmunity. If both tests for adrenal autoimmunity, as measured by indirect immunofluorescence and 21-hydroxylase immunoprecipitation, are negative at the initial examination, a reasonable strategy is not to repeat the testing unless it is otherwise clinically indicated. However, all patients with primary ovarian insufficiency should be educated regarding the symptoms of adrenal insufficiency and should undergo evaluation of adrenal function if such symptoms develop.
There is an increased incidence of the dry-eye syndrome and ocular-surface disease in women with primary ovarian insufficiency, as compared with controls (20% vs. 3%), and women who have either of these disorders benefit from referral to an ophthalmologist.18 Thyroid autoimmune disease, most commonly Hashimoto's thyroiditis, is present in 14 to 27% of women19,44 at initial diagnosis. It is reasonable to measure thyrotropin levels and test for the presence of thyroid peroxidase antibodies. Other autoimmune disorders, such as myasthenia gravis, rheumatoid arthritis, and systemic lupus erythematosus, have also been reported in association with primary ovarian insufficiency,19 but such cases are infrequent, and testing for these and other autoimmune conditions should be predicated on symptoms and signs that are suggestive of the condition.

Family Planning
Patients who wish to avoid pregnancy should use a barrier method or possibly an intrauterine device. The effectiveness of oral contraceptives has not been studied in women with primary ovarian insufficiency, and there are anecdotal reports of women who have conceived while complying with the oral contraceptive regimen,45 perhaps because of a failure of the oral contraceptive to suppress the high FSH levels that are characteristic of this condition.
Patients should understand that spontaneous remission resulting in pregnancy occurs in 5 to 10% of cases.8 Generally, remissions are temporary, but they may (although rarely) last for years.5 Currently, there are no known markers that are associated with an increased rate of remission, and there are no therapies that have been shown to restore ovarian function and fertility. Some couples are averse to adoption and to reproductive technologies and are content not to become parents or to accept the low but real chance that the infertility will resolve spontaneously. For couples who decide to pursue parenthood actively, the options are adoption, foster parenthood, egg donation, and embryo donation; ovarian transplantation has been performed in rare cases in which the patient has an identical twin with normal ovarian function.46 There is no medical urgency to proceed to egg donation, because the rates of pregnancy with egg donation appear to be similar among older and younger women.47 Women with primary ovarian insufficiency who become pregnant as a result of oocyte donation may have an increased risk of delivering infants who are small for gestational age and of having pregnancy-induced hypertension and postpartum hemorrhage,48-50 but these findings are controversial.51

AREAS OF UNCERTAINTY
Studies involving women with the FMR1 premutation have established that this mechanism of primary ovarian insufficiency is associated with a clinical spectrum of impaired ovarian function that involves a continuum of occult, biochemical, and overt ovarian insufficiency; a better understanding is needed of the spectrum of disease associated with other causes of primary ovarian insufficiency

In addition, research is needed on strategies to improve fertility for women who have follicles remaining in the ovary. The magnitude of long-term risks associated with the disorder (including cardiovascular disease and osteoporosis) and the optimal means of reducing these risks are uncertain.

GUIDELINES
Several professional organizations recommend that women with primary ovarian insufficiency undergo testing for a premutation in the FMR1 gene.55-57 The American Society for Reproductive Medicine and the International Menopause Society recommend estrogen-replacement therapy for women with primary ovarian insufficiency.14,58

ONCLUSIONS AND RECOMMENDATIONS
The woman in the vignette has amenorrhea and a menopausal FSH level. Confirmation of the elevated FSH level and a low estradiol level would confirm the diagnosis of primary ovarian insufficiency. This information is highly emotionally charged and should be discussed with the patient at a return visit to the office rather than by telephone, with recognition of the emotional effect of the diagnosis. Patients should understand that remission may occur and that pregnancy, though unlikely, occurs in 5 to 10% of cases. A karyotype analysis, tests for the FMR1 premutation and adrenal autoimmunity, a pelvic ultrasound examination, and measurement of bone mineral density are indicated at the time of diagnosis. Women with primary ovarian insufficiency should be encouraged to maintain a lifestyle that optimizes bone and cardiovascular health, including engaging in regular weight-bearing exercise, maintaining an adequate intake of calcium (1200 mg daily) and vitamin D (at least 800 IU daily), eating a healthy diet to avoid obesity, and undergoing screening for cardiovascular risk factors, with treatment of any identified risk factors. Although there are no data from randomized trials to guide the use of hormonal therapy in women with this condition, a reasonable regimen would be 100 μg of transdermal estradiol and 10 mg of oral medroxyprogesterone acetate daily for the first 12 days of each month. Women should keep a menstrual calendar and have a pregnancy test promptly in the case of late menses.




History


Investigations


Management

Menstrual disorders

Normal menstrual bleeding at the end of an ovulatory cycle results from estrogen-progesterone withdrawal. The same mechanism operates when the corpus luteum is removed or when its gonadotropin support is suddenly interrupted during the luteal phase. Other examples include the bleeding that follows discontinuation of both estrogen and progestin in women receiving cyclic postmenopausal hormone therapy and the bleeding that comes at the end of a standard cycle of oral contraceptives. Under these circumstances, bleeding generally is regular, predictable, and consistent in volume and duration. However, estrogen-progesterone withdrawal is not the only pattern of steroid hormone signals that can provoke endometrial bleeding. Bleeding can also result from estrogen withdrawal, estrogen breakthrough, progesterone withdrawal, and progesterone breakthrough.
Estrogen Withdrawal Bleeding
One clinical example of estrogen withdrawal bleeding is that which may follow bilateral oophorectomy during the follicular phase of the cycle. The bleeding that occurs after removal of the ovaries can be delayed by exogenous estrogen therapy, but will occur when treatment stops. Other examples include cyclic estrogen-only hormone therapy in castrate or postmenopausal women and the midcycle bleeding that coincides with the transient but abrupt fall in estrogen levels immediately before ovulation.
Estrogen Breakthrough Bleeding
The best clinical examples of estrogen breakthrough bleeding are the different patterns of bleeding observed in women with chronic anovulation. The amount and duration of estrogen breakthrough bleeding can vary widely, depending on the amount and duration of unopposed estrogen stimulation that the endometrium has received. Relatively low levels of chronic estrogen exposure typically result in intermittent spotting or staining that is generally light in volume but may be prolonged. In contrast, sustained high level estrogen stimulation commonly results in long intervals of amenorrhea punctuated by acute episodes of often profuse bleeding that vary in duration.
Progesterone Withdrawal Bleeding
Progesterone withdrawal bleeding is observed when treatment with exogenous progesterone or a synthetic progestin is discontinued. Progesterone withdrawal bleeding usually occurs only when the endometrium has first been primed with endogenous or exogenous estrogen. The amount and duration of bleeding can vary widely and generally correlates with the level and duration of previous estrogen-stimulated endometrial proliferation. In women with marginal to frankly low estrogen levels or short intervals of amenorrhea, bleeding is generally light to scant and may not occur at all. In those with
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sustained high estrogen levels or long intervals of amenorrhea, bleeding can be heavy and somewhat prolonged, but is still self-limited. Between the extremes, the amount and duration of bleeding induced by progesterone withdrawal is typically similar to that observed at the end of a normal ovulatory cycle. In women receiving cyclic hormone therapy with exogenous estrogen and progestin, bleeding follows withdrawal of progesterone even if estrogen treatment continues; progestin withdrawal bleeding can be delayed, but only if estrogen levels are increased 10–20-fold.45
Progesterone Breakthrough Bleeding
Progesterone breakthrough bleeding occurs when the ratio of progesterone to estrogen is unfavorably high. Unless there is sufficient estrogen to balance its action, continuous treatment with exogenous progesterone or synthetic progestins results in intermittent bleeding of varying duration that is generally light, a pattern very similar to low level estrogen breakthrough bleeding described above. Clinical examples of progesterone breakthrough bleeding are the bleeding observed in women using the progestin-only contraceptive “mini-pill” or other long-acting progestin-only contraceptive methods (progestin implants, depot medroxyprogesterone acetate).46 The breakthrough bleeding observed in women using combination estrogen-progestin oral contraceptives is also a form of progesterone breakthrough bleeding. Although all standard oral contraceptive pill regimens contain pharmacologic quantities of both estrogen and progestin, the progestin component is always the dominant hormone and the net effect of oral contraceptives on the endometrium is profoundly progestational


Anovulatory Bleeding
Part of "15 - Dysfunctional Uterine Bleeding"
Anovulatory bleeding can represent estrogen withdrawal bleeding, reflecting the transient fall in estrogen levels resulting from regression of the most recent follicular cohort, or estrogen breakthrough bleeding due to focal breakdown of an overgrown and structurally fragile endometrium under continuous estrogen stimulation. The heaviest episodes of anovulatory bleeding tend to occur in women with sustained high levels of estrogen; women with polycystic ovary syndrome, obese women, postmenarcheal adolescents, and perimenopausal women are common clinical examples. The clinical presentation spans the spectrum from the pale, frightened teenager who has bled for weeks to the older woman who is deeply concerned that she may have cancer.
In contrast to the organized predictable pattern of sequential estrogen-progesterone stimulation and withdrawal that characterizes the normal ovulatory menstrual cycle, the patterns of ovarian steroid hormone production and endometrial stimulation in anovulatory women are disorganized and unpredictable. By definition, the anovulatory woman is always in the follicular phase of the ovarian cycle and in the proliferative phase of the endometrial cycle. There is no luteal or secretory phase because there is no cycle. The only ovarian steroid signal the endometrium receives is estrogen, levels, which constantly fluctuate, rising and falling as each new cohort of follicles begins to grow but ultimately loses its developmental momentum, sooner or later, and lapses into atresia. Although the amplitude of the signal may vary, the message, growth, stays the same.
Over a period of time, an unrelenting, uninterrupted estrogen growth stimulus can stimulate the endometrium to proliferate to abnormal heights where it becomes fragile. Without the growth limiting and organizing effects of progesterone, the endometrium lacks the stromal support structure to maintain stability. Focal areas breakdown and bleed and, as those areas heal under the influence of continued estrogen stimulation, others break down and bleed. Persistent proliferative and hyperplastic endometrium characteristically exhibits numerous discrete foci of stromal breakdown near the epithelial surface, associated with pools of extravasated red blood cells, capillary platelet/fibrin thrombi, and repair-related changes recognized as ball-like aggregates of tightly packed stromal cells beneath a cap of intact but hypertrophied epithelium.24 The cause for the focal breakdowns in persistent proliferative endometrium is not entirely clear. However, abnormal endometrial growth involves not only epithelial and stromal cells but also the microvasculature.
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Venous capillaries in persistent proliferative and hyperplastic endometrium are increased, dilated, and often form abnormal irregular channels; ultrastructural studies have revealed a number of abnormal structural elements that predispose to fragility.47, 48 The abnormal microvasculature could be the result, but is more likely the proximate cause of abnormal bleeding. The weight of available evidence from histologic and molecular studies indicates that anovulatory bleeding results from an increased density of abnormal vessels having a fragile structure prone to focal rupture, followed by release of lysosomal proteolytic enzymes from surrounding epithelial and stromal cells and migratory leukocytes and macrophages. Once initiated, the process is further aggravated by local release of prostaglandins, with greater sensitivity to those that vasodilate (PGE2) than to those that vasoconstrict (PGF2α).49 Other molecules (perforins) inhibit capillary plug formation and further degrade the capillary venous network. Vasoconstriction of basal endometrial and superficial myometrial vessels does not occur because tissue loss is only focal and superficial, and does not typically reach the basal layer where denudation triggers an intense vasoconstrictive response. The final mechanism that normally controls menstrual bleeding, surface epithelial reconstruction, operates in persistent proliferative endometrium, but not in a normal way. Epithelial repair is focal, in the areas of breakdown, not universal; the result is a constantly changing patchwork of small repairs instead of an organized and well structured remodeling.24
Traditional Definitions
Oligomenorrhea: Intervals greater than 35 days.
Polymenorrhea: Intervals less than 24 days.
Menorrhagia: Regular normal intervals, excessive flow or duration.
Metrorrhagia: Irregular intervals, excessive flow or duration.

Diagnostic Evaluation of Abnormal Bleeding
Part of "15 - Dysfunctional Uterine Bleeding"
A careful menstrual history is the single most useful tool in differentiating anovulatory bleeding from other causes. Detailed information regarding intermenstrual intervals (number of days, regularity), volume (heavy, light, or variable), duration (normal or prolonged, consistent or variable), the onset of abnormal menses (perimenarcheal, sudden, gradual), temporal associations (postcoital, postpartum, postpill, weight gain or loss), associated symptoms (premenstrual molimina, dysmenorrhea, dyspareunia, galactorrhea, hirsutism), underlying systemic illnesses (renal, hepatic, hematopoietic, thyroid), and medications (hormonal, anticoagulants) can provide important clues and help to quickly determine whether additional evaluation is needed before treatment begins. Physical examination should exclude visible vaginal or cervical lesions and define uterine size (normal or enlarged), contours (smooth and symmetrical or irregular), consistency (firm or soft), and tenderness.
In the majority of women with true anovulatory bleeding, menstrual history alone can establish the diagnosis with sufficient confidence that treatment can begin without additional laboratory evaluation or imaging. Infrequent, irregular, unpredictable menstrual bleeding that varies in amount, duration, and character and is not preceded by any recognizable or consistent pattern of premenstrual molimina generally is not difficult to interpret. Conversely, regular monthly periods that are heavy or prolonged are more likely related to an anatomical lesion or a bleeding disorder than to anovulation.
Laboratory tests can be helpful but are not always necessary. A sensitive pregnancy test can quickly exclude any realistic possibility that the bleeding relates to an accident or complication of pregnancy. A complete blood count to exclude anemia and thrombocytopenia is prudent in women with a history of prolonged or extremely heavy bleeding. A well-timed serum progesterone determination during what should be the luteal phase of the cycle can help to document ovulation or anovulation, when doubt exists; any value greater than 3 ng/mL provides reliable evidence that ovulation has recently occurred.68 However, when bleeding episodes are frequent or poorly documented, proper timing for a progesterone measurement can be difficult to determine. In anovulatory women, a serum thyroid-stimulating hormone (TSH) level can quickly exclude any associated thyroid disorder. In adolescents, those with a suspicious personal or family history, and those with unexplained menorrhagia, suspicion of a bleeding disorder is sufficient indication for screening coagulation studies.54, 69 The ristocetin cofactor assay for the von Willebrand's factor function may be the best single screening test for von Willebrand's disease,69, 70, 71 but consultation with a hematologist is recommended because test methods, preferences, and interpretation vary.72, 73 Liver or renal function tests are indicated only for those with known or strongly suspected disease.
Office aspiration biopsy can exclude endometrial hyperplasia or cancer. Age 40 years and over is an established risk factor for endometrial disease and widely cited as an indication for biopsy in women with abnormal bleeding. Endometrial hyperplasia and cancer are more commonly detected in older than in younger women, but duration of exposure to unopposed estrogen stimulation is the more critical risk
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factor. Long-term exposure is more likely in older than in younger women, but women under age 30 and even teenagers can develop endometrial cancer.74, 75, 76, 77 In premenopausal women, the likelihood of abnormal endometrial histology is relatively high (14%) when menses are irregular but very low (less than 1%) when cycles are regular.78 The small flexible suction cannulas now widely available cause less discomfort than older traditional biopsy instruments and yield comparable results.79, 80, 81 In addition to revealing any intrinsic endometrial disease, biopsy can help to direct further evaluation or to guide the choice of treatment in women with a confusing history of abnormal bleeding. In women with abnormal bleeding and no recent exposure to exogenous progestational agents, a secretory endometrium provides reliable evidence of recent ovulation and signals the need to search for an anatomical cause.
Uterine imaging can help to differentiate anovulatory bleeding from anatomic causes, myomas and endometrial polyps being by far the most common examples of the latter. Standard transvaginal ultrasound examination can provide accurate information about the size and location of any uterine fibroids that may explain abnormal bleeding or exaggerate the bleeding due to other causes.82
Ultrasound may reveal an obvious cavitary lesion or an abnormally thin or thick endometrial “stripe.” A very thin endometrial stripe (less than 5 mm), like a biopsy that yields minimal or no tissue, suggests an attenuated or denuded endometrium best treated first with estrogen rather than with a progestin or an estrogen-progestin combination (discussed later). In perimenopausal and postmenopausal women with abnormal bleeding, endometrial biopsy is widely considered unnecessary when the endometrial thickness is less than 4 or 5 mm because the risk of endometrial hyperplasia or cancer is remote.83, 84, 85 It seems logical to apply the same criteria for the same reason in premenopausal women with abnormal bleeding, although there is no substantial direct evidence to support the extrapolation. Otherwise, the decision to biopsy or not should be based primarily on clinical suspicion and risk factors rather than on ultrasound measurements of endometrial thickness. That does not mean that endometrial thickness has no bearing on the decision whether to perform a biopsy; a grossly increased endometrial thickness (greater than 12 mm) increases the risk of disease and is an indication for sampling, even when clinical suspicion of pathology is otherwise low.86 In summary, we believe that biopsy is unnecessary when the endometrial thickness is less than 5 mm, that biopsy is indicated when the clinical history suggests long-term unopposed estrogen exposure even when the endometrial thickness is “normal” (5–12 mm), and that biopsy should be performed when endometrial thickness is greater than 12 mm even when clinical suspicion of disease is low.
Sonohysterography, involving transvaginal ultrasound during or after introduction of sterile saline with any of a variety of available catheters (also known as hydrosonography and saline infusion sonography) sharply defines cavity contours and readily demonstrates even small intrauterine lesions; the sensitivity and specificity of sonohysterography exceed that of standard transvaginal ultrasound and compare favorably with hysteroscopy.87, 88, 90 The combination of sonohysterography and endometrial biopsy offers a high sensitivity and high negative predictive value for detection of endometrial and uterine pathology in women with abnormal bleeding.91
Hysteroscopy is the definitive method for both diagnosis and treatment of symptomatic intrauterine pathology but also clearly the most invasive. Traditionally, hysteroscopy has been reserved for treatment of disease identified by other less invasive methods, but modern operative hysteroscopes having an outer diameter of 2 or 3 mm now permit diagnostic and minor operative procedures to be performed in the office setting.92 Major intrauterine pathology generally requires more traditional operative hysteroscopy using instruments having a larger caliber and greater capabilities.
In general, diagnostic uterine imaging can be reserved for those women in whom the menstrual history or the results of other evaluation provide strong evidence for an anatomic cause of abnormal bleeding, including any of the following.
Regular monthly cycles with increasing volume or duration of bleeding.
Regular monthly cycles complicated by intermenstrual bleeding in the absence of a vaginal or cervical lesion.
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Abnormal bleeding despite objective evidence of ovulation from measurement of serum progesterone (more than 3 ng/mL) or from endometrial biopsy (secretory endometrium).
Failed empirical medical management.
As in all aspects of clinical medicine, the success of treatment hinges on an accurate diagnosis. When there is good reason to suspect a coagulopathy or uterine pathology as the cause of abnormal bleeding, diagnostic laboratory tests, endometrial biopsy, or uterine imaging should be carefully considered before beginning empiric medical management. When there is every reason to believe that anovulation is the cause, empiric medical management based on that premise is entirely reasonable, but one should also expect a prompt resolution of the problem with treatment. When bleeding persists despite appropriate empiric medical management, further diagnostic evaluation is likely to be more productive than a higher dose or otherwise different medical treatment regimen.

Chronic pelvic pain : history taking and investigations

http://www.uptodate.com/patients/content/topic.do?topicKey=~777HbAIIypxfsO

Gynecologic causes — Gynecologic causes are thought to be the cause of chronic pelvic pain in about 20 percent of women. Some of the gynecologic causes of pelvic pain include:

Endometriosis — The tissue lining the inside of the uterus is called the endometrium (picture 1). Endometriosis is a condition in which endometrial tissue is also present outside of the uterus. Some women with endometriosis have no symptoms, while others experience marked discomfort and pain and may have problems with fertility. (See "Patient information: Endometriosis" and "Patient information: Evaluation of the infertile couple".)

Chronic pelvic inflammatory disease — Pelvic inflammatory disease is an infection caused by a sexually transmitted organism. Occasionally, it is caused by a previous ruptured appendix or scarring resulting from previous pelvic surgery. It can involve the uterus, ovaries, and fallopian tubes (which link the ovaries and uterus) (picture 1). Pelvic inflammatory disease can cause pain, abnormal uterine bleeding, and symptoms of infection such as fever and chills. (See "Patient information: Gonorrhea" and "Patient information: Chlamydia".)

Other causes — Non-gynecologic causes of chronic pelvic pain may be related to the digestive system, urinary system, or to pain in the muscles and nerves in the pelvis:

Irritable bowel syndrome — Irritable bowel syndrome is a gastrointestinal condition characterized by chronic abdominal pain and altered bowel habits (such as loose stools, more frequent bowel movements with onset of pain, and pain relieved by defecation) in the absence of any specific cause. (See "Patient information: Irritable bowel syndrome".)

Painful bladder syndrome and interstitial cystitis — Painful bladder syndrome and interstitial cystitis (PBS/IC) are the terms given to pain in the tissues in the bladder and surrounding nerves and muscles that is not caused by infection. Symptoms usually include the need to urinate frequently (frequency) and a feeling of urgently needing to urinate (urgency). Some women with painful bladder syndrome have lower abdominal or pelvic pain in addition to urinary tract symptoms. A separate topic review is available that discusses PBS/IC. (See "Patient information: Painful bladder syndrome and interstitial cystitis".)

Diverticulitis — A diverticulum is a sac-like protrusion that sometimes forms in the muscular wall of the colon (or intestine). Diverticulitis occurs when diverticula become inflamed. This usually causes abdominal pain; nausea and vomiting, constipation, diarrhea, and urinary symptoms can also occur. (See "Patient information: Diverticular disease".)

Pelvic floor pain — The muscles of the pelvic floor can sometimes become shortened, tight and tender; this is called pelvic floor dysfunction. The pelvic floor includes muscles that attach to the pelvic bones and sacrum (lower part of the spine). Normally, these muscles function to support the hips and pelvic organs. It is not clear why this problem develops.

Symptoms may include pelvic pain, pain with urination, constipation, pain with intercourse, or frequent/urgent urination. Pelvic floor dysfunction can be diagnosed by a clinician feeling the muscles in the vagina and/or rectum; muscles that feel tight, tender, or band-like indicate that pelvic floor dysfunction could be contributing to pelvic pain.

Fibromyalgia — Fibromyalgia is one of a group of chronic pain disorders that affect connective tissue structures, including muscles, ligaments, and tendons. It is characterized by widespread muscle pain (or "myalgia") and tenderness in certain areas of the body. Women with fibromyalgia may also experience fatigue, sleep disturbances, headaches, and mood disturbances such as depression and anxiety. (See "Patient information: Fibromyalgia".)

DIAGNOSIS OF THE CAUSE OF CHRONIC PELVIC PAIN

Because a number of different conditions can cause chronic pelvic pain, it is sometimes difficult to pinpoint the specific cause.

History and physical examination — A thorough history and a physical examination of the abdomen and pelvis are essential components of the work-up for women with pelvic pain. In particular, the examination should include the lower back, abdomen, hips, and pelvis (internal examination).

Laboratory tests, including a white blood cell count, urine analysis, tests for sexually transmitted infections, and a pregnancy test may be recommended, depending upon the results of the physical examination.

Pelvic ultrasound — Some diagnostic procedures may also be helpful in identifying the cause of chronic pelvic pain. As an example, a pelvic ultrasound examination is accurate in detecting pelvic masses, including ovarian cysts (sometimes caused by ovarian endometriosis) and uterine fibroids. However, ultrasound is not helpful in the diagnosis of irritable bowel syndrome, diverticulitis, or painful bladder syndrome.

Laparoscopy — A surgical procedure called a laparoscopy may be helpful in diagnosing some causes of chronic pelvic pain such as endometriosis and chronic pelvic inflammatory disease. Laparoscopy is a procedure that is often done as a day surgery. Most women are given general anesthesia to induce sleep and prevent pain. A thin telescope with a camera is inserted through a small incision just below the navel. Through the telescope, the surgeon can see the contents of the abdomen, especially the reproductive organs. If the laparoscopy is normal, the physician can then focus the diagnostic and treatment efforts on non-gynecologic causes of pelvic pain.

If the laparoscopy is abnormal (eg, areas of endometriosis or abnormal tissue are seen) these areas may be treated or biopsied during the procedure.

COPING WITH CHRONIC PELVIC PAIN

Psychological counseling may be offered to help women manage their pelvic pain. There are several types of psychosocial support:

Psychotherapy involves meeting with a psychologist, psychiatrist, or social worker to discuss emotional responses to living with chronic pain, treatment successes or failures, and/or personal relationships.
Group psychotherapy allows people to compare their experiences with PBS/IC, overcome the tendency to withdraw and become isolated in pain, and support one another's attempts at more effective management.
Online or local support groups that deal with chronic pain may also be helpful, such as the American Chronic Pain Society (www.theacpa.org) and the American Academy of Pain Management (www.aapainmanage.org/links/Links.php).
Relaxation techniques can relieve musculoskeletal tension, and may include meditation, progressive muscle relaxation, self-hypnosis, or biofeedback.
CHRONIC PELVIC PAIN TREATMENT

Chronic pelvic pain due to a gynecologic condition is often treated medically. In some cases, however, surgery may be the treatment of choice.

Medical treatment — Medication may be prescribed once laboratory and imaging tests suggest the pain is due to a gynecologic condition. Drugs that may be used include:

Nonsteroidal anti-inflammatory medications such as ibuprofen
Hormonal birth control methods (eg, pill, patch, vaginal ring) may be taken so that the woman has a monthly menstrual period or so that the woman only has a period every three to four months. (See "Patient information: Hormonal methods of birth control".)
Doxycycline, an antibiotic used to treat some causes of pelvic inflammatory disease.
Medications called gonadotropin releasing hormone (GnRH) agonist analogues used to treat endometriosis. (See "Patient information: Endometriosis".)
Physical therapy — Pelvic floor physical therapy (PT) is often helpful for women with tight and tender pelvic muscles. This type of PT aims to release the tightness in these muscles by manually "releasing" the tightness; treatment is directed to the muscles in the vagina, hips, thighs, and lower back. Physical therapists who perform this type of PT must be specially trained. (See "Patient information: Treatment of painful bladder syndrome and interstitial cystitis".)

Pain management clinics — If medications are not effective in treating the pain, a woman may be referred to a medical practice specializing in pain management. Pain services utilize multiple treatment modalities including

Acupuncture
Biofeedback and relaxation therapies
Nerve stimulation devices
Injection of tender sites with a local anesthetic (eg, lidocaine, marcaine)
Pain services can help women who have become dependent on narcotics for pain management.

Surgical treatment — A few causes of gynecologic pelvic pain can be treated surgically. For example, some women benefit from surgical removal of their endometriosis.

Hysterectomy may alleviate chronic pelvic pain, especially when it is due to uterine disorders such as adenomyosis or fibroids. However, pain can persist even after hysterectomy, particularly in younger women (those less than 30) and in women with a history of chronic pelvic inflammatory disease or pelvic floor dysfunction. Hysterectomy is not a good choice for the management of chronic pelvic pain in women who have not completed their family. (See "Patient information: Abdominal hysterectomy" and "Patient information: Vaginal hysterectomy".)

Surgery to cut some of the nerves in the pelvis has also been studied as a treatment for chronic pelvic pain. However, this approach has not proven to be effective for most women.

WHERE TO GET MORE INFORMATION

Your healthcare provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed every four months on our web site (www.uptodate.com/patients).

Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.

Patient level information

Patient information: Endometriosis
Patient information: Evaluation of the infertile couple
Patient information: Gonorrhea
Patient information: Chlamydia
Patient information: Irritable bowel syndrome
Patient information: Painful bladder syndrome and interstitial cystitis
Patient information: Diverticular disease
Patient information: Fibromyalgia
Patient information: Hormonal methods of birth control
Patient information: Treatment of painful bladder syndrome and interstitial cystitis
Patient information: Abdominal hysterectomy
Patient information: Vaginal hysterectomy

Professional level information

Causes of chronic pelvic pain in women
Chronic prostatitis/chronic pelvic pain syndrome
Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis
Diagnostic approach to abdominal pain in adults
Differential diagnosis of abdominal pain in adults
Evaluation of chronic pelvic pain in women
Pathogenesis, clinical manifestations, and diagnosis of primary dysmenorrhea in adult women
Treatment of chronic pelvic pain in women
Treatment of painful bladder syndrome/interstitial cystitis
Treatment of primary dysmenorrhea in adult women

The following organizations also provide reliable health information.

National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)

The International Pelvic Pain Society
(www.pelvicpain.org)

The Mayo Clinic
(www.mayoclinic.com)

US Department of Health and Social Services
(www.4woman.gov, search for pelvic pain)

Investigations for primary subfertility

Algorithm : http://www.nice.org.uk/nicemedia/live/10936/29268/29268.pdf

Full guidance :http://www.nice.org.uk/nicemedia/live/10936/29267/29267.pdf