Women report an irregular menstrual cycle, abnormally long periods of time between two menstruation periods or absence of menstruation bleedings for months. They may present additional symptoms that facilitate localization of the disturbance:

• Hypothalamic or pituitary gland disorders may be due to a tumor impairing function of these organs. This could manifest in form of headaches.
• Also, head injury or infections of the central nervous system may have interrupted superordinate regulatory mechanisms and should be asked for.
• Prolactine is essential for lactation and suppresses the menstrual cycle. Hyperprolactinemia is caused by pituitary diseases and also leads to galactorrhea.
• Dysmenorrhea, painful menses due to abdominal cramps, point at a problem at ovarial or uterine level.
• Similarly, a medical history of recent diseases of the reproductive tract and possibly therapeutic intervention may cause intrauterine adhesions and trigger Asherman's syndrome.

Furthermore, hints as to the cause of SA may be found in the patient's clinical history and in a general clinical examination. In this context, a history of anti-psychotic or opioid medication may explain amenorrhea as well as long-acting depot contraceptives. Chronic systemic diseases and a poor overall condition, particularly when related to loss of appetite, anorexia and weight loss, may significantly diminish fertility and cause SA. Eating disorders and emotional stress may not yet manifest in such severe symptoms, but may already delay menses by triggering hypothalamic dysfunction and subsequent hypogonadotrophic hypogonadism (group I SA patients). Of note, extreme athleticism and abnormally low body weight may cause similar pathophysiological events [7].

• Weakness

  […] amenorrhea ( ↓ LH/ ↓ FSH) Loss of libido Increased sensitivity to cold (hypothyroidism) ( ↓ TSH) Signs: Loss of axillary and pubic hair (Signs of adrenal cortical failure) Decrease in skin pigmentation Anemia due to lack of pituitary erythropoeitic factor Weakness [gradestack.com]

  Other symptoms include menstrual irregularities, hirsutism, impaired glucose metabolism and diabetes, hypertension, proximal muscle weakness and atrophy, fatigue, and neuropsychological symptoms such as depression and mood instability ( 5 ). [clinchem.org]

  Cushing’s disease is rare; therefore, patients should only be screened when characteristic signs and symptoms (e.g., striae, buffalo hump, significant central obesity, easy bruising, hypertension, proximal muscle weakness) are present. 21, 22 View/Print [aafp.org]

• Heart Disease

  Untreated, hypothalamic amenorrhea can lead to continued problems with infertility as well as osteoporosis and heart disease. [azfertility.com]

  If left untreated and not diagnosed it can also lead to diabetes and heart disease. Pelvic Inflammatory disease (PID) This is an infection of the reproductive organs in women. [info.isabelhealthcare.com]

  Does age at natural menopause affect mortality from ischemic heart disease?. J Clin Epidemiol. 1997;50:475–9. 32. Kim TJ, Anasti JN, Flack MR, Kimzey LM, Defensor RA, Nelson LM. [aafp.org]

• Hypotension

  Virilization Polycystic ovary syndrome Low body mass index (eg, 18.5 kg/m 2 ) Risk factors such as a chronic disorder, dieting, or an eating disorder Functional hypothalamic anovulation Hypothermia, bradycardia, other arrhythmias and/or palpitations, hypotension [merckmanuals.com]

  Sheehan’s syndrome, characterized by postpartum amenorrhea, results from postpartum pituitary necrosis secondary to severe hemorrhage and hypotension. [fogsi.org]

• Increased Muscle Mass

  General examination focuses on evidence of virilization, including hirsutism, temporal balding, acne, voice deepening, increased muscle mass, clitoromegaly (clitoral enlargement), and defeminization (a decrease in previously normal secondary sexual characteristics [merckmanuals.com]

• No Pubic Hair

  View/Print Table TABLE 1 Normal Female Pubertal Development Developmental stage (age in years) Anatomic drawing Tanner stage Breast development Pubic hair development Initial growth acceleration (8 to 10) Elevation of papilla only; no pubic hair 1 1 Thelarche [aafp.org]

  Secondary sexual characteristics are evaluated; breast and pubic hair development are staged using the Tanner method. If axillary and pubic hair is present, adrenarche has occurred. [merckmanuals.com]

  Clinical Features Symptoms Failure of lactation after delivery (due to ↓ Prolactin) Secondary amenorrhea ( ↓ LH/ ↓ FSH) Loss of libido Increased sensitivity to cold (hypothyroidism) ( ↓ TSH) Signs: Loss of axillary and pubic hair (Signs of adrenal cortical [gradestack.com]

  Primary amenorrhea is the absence of menstrual bleeding and secondary sexual characteristics (for example, breast development and pubic hair) in a girl by age 14 years or the absence of menstrual bleeding with normal development of secondary sexual characteristics [emedicinehealth.com]

• Fear

  KEY TERMS Anorexia nervosa —An eating disorder marked by an unrealistic fear of weight gain, self-starvation, and distortion of body image. It most commonly occurs in adolescent females. [healthofchildren.com]

  KEY TERMS Anorexia nervosa — An eating disorder marked by an unrealistic fear of weight gain, self-starvation, and distortion of body image. It most commonly occurs in adolescent females. [encyclopedia.com]

  Generally, women seek medical attention because of amenorrhea for two reasons: concern for fertility and fear that amenorrhea may be a symptom of some serious underlying disease. [glowm.com]

• Amenorrhea

  A young patient with secondary amenorrhea and primary infertility is described. [ncbi.nlm.nih.gov]

• Secondary Amenorrhea

  A young patient with secondary amenorrhea and primary infertility is described. [ncbi.nlm.nih.gov]

Because the most common cause for SA is pregnancy, a corresponding test should be done on blood or urine samples of affected women.

Consecutively, hormone levels should be measured in serum samples. Concentrations of FSH, prolactin and estradiol give valuable hints as to the localization of the problem. These values allow classification of SA as proposed by the World Health Organization and described in one of the previous chapters.

In detail, low levels of FSH and hyperprolactinemia suggest a hypothalamic or pituitary gland functional impairment. Neuroimaging techniques are to be applied in order to rule out neoplasms, unless iatrogenic causes can be identified for this condition.

Elevated concentrations of FSH combined with low estrogen levels are encountered in women suffering from primary, premature ovarian failure. This diagnosis should be supplemented with genetic tests in young women. Also, permanently low estrogen levels should prompt bone density measurements.

If all these values are within their normal range, androgen levels may support diagnosis of polycystic ovary syndrome. Women affected by this disease often show hyperandrogenism. Androgen-producing tumors, e.g., adrenal adenoma, have to be considered as differential diagnoses should increased values be measured.

Additionally, serum levels of thyroid-stimulating hormone (TSH), also produced by the anterior pituitary, should be assessed. TSH release depends on thyrotropin-releasing hormone (TRH) and increased production of TRH also augments prolactin release. As has been mentioned above, prolactin suppresses the menstrual cycle. On the other hand, diminished TSH levels may result from hyperthyroidism, an endocrinological disorder that may lead to oligomenorrhea or SA.

These evaluations should be complemented by a gynecological examination and transabdominal or transvaginal sonography. Imaging helps to assess the condition of ovaries and uterus, may reveal anatomical anomalies and may help to confirm or refute previously suspected diagnoses. More detailed images may be obtained by magnetic resonance imaging.

Nowadays, progesterone withdrawal tests, in former times used frequently, are rarely necessary because serum estrogen levels provide similar information.

Only when the cause of SA has been identified can treatment options be chosen. In this context, psychological treatment is recommended for eating disorders and may be helpful in case of obesity. Here, weight reduction should be the first goal. Drug-induced amenorrhea may be counteracted by cessation or change of drug administration, if reasonable. Underlying endocrinological disturbances, e.g., thyroid abnormalities, need to be treated. If these result from Turner syndrome, dysfunctions of other organ systems require further therapy [8]. Adequate surgical or drug therapy is indicated in cases of hypothalamic or pituitary tumors. Surgical intervention may also be the therapy of choice for Asherman's syndrome and other anatomical anomalies.

Additionally, hormone replacement therapy is indicated in women at risk or diagnosed with reduced bone density. If the physiological menstrual cycle cannot be re-established, it should be prolonged until the age of menopause [9]. Patients should be advised regarding dietary measures to assure sufficient calcium and vitamin D uptake.

In cases of non-treatable underlying diseases or persisting amenorrhea after supposed successful cure, women should be referred to a fertility clinic in order to fulfill their desire to have children.

Of note, there is a slight chance to become pregnant despite of being diagnosed with SA, so contraception should be continuously used.

Prognosis for fertility and overall health depend on the underlying disease. In this context, dietary factors, behavioral disorders and a variety of primary endocrinological disturbances are curable, whereas premature ovarian failure and follicle depletion are more difficult to treat. Follicle depletion may indeed be the cause of irreversible infertility.

While fertility may be a great concern of young women, there are several comorbidities associated with SA. Estrogens and other sexual hormones do not only affect functioning of the reproductive system, but also play a very important role in establishing and maintaining physiological bone density. Significant augments of bone mass occur in adolescence and either late menarche, primary amenorrhea or SA at this age contribute to an increase in the risk of bone fractures [5]. These conditions therefore require hormone replacement therapy. Similarly, adult women may suffer the consequences of low estrogen levels. Oligomenorrhea as well as amenorrhea increment their risk of wrist and hip fractures.

Women pertaining to group II of SA patients, those presenting with polycystic ovary syndrome, often develop additional metabolic disorders, e.g., obesity and dermatological problems [6].

A variety of hormones accounts for onset, cessation or absence of the menstruation. In detail, altered levels of gonadotropins and prolactin, both released by the anterior pituitary, as well as estrogens, produced in the ovaries, may trigger SA. Based on this, the World Health Organization has proposed the following causative classification of SA:

• Group I. These patients do not present any alterations of the hypothalamic regulation of pituitary activity, but follicle-stimulating hormone (FSH) levels nevertheless remain low and subsequently, low quantities of estrogens are produced. Prolactin levels may be elevated. Here, hypogonadotrophic hypogonadism accounts for SA. Of note, a significant share of group I SA patients presents rare gene variants and thus, genetic factors may contribute to this form of SA.
• Group II. Superordinate regulatory mechanisms, i.e., hypothalamus and anterior pituitary, are unaltered, FSH and prolactin levels are in their normal ranges. Estrogen levels are physiologically, too. This condition is characteristic for polycystic ovary syndrome.
• Group III. This group demonstrates hormone levels similar to those observed in group II, but estrogen levels are decreased. This leads to the diagnosis of premature ovarial failure and this group accounts for 10% of all SA patients.

Although these three groups comprise a large share of SA patients, this classification is not complete. Behavioral disturbances, for instance, may also account for SA and are not mentioned at all. It must be said that such patients may nevertheless fall into any of these three groups because behavioral disorders may cause SA by means of endocrinological disturbances. In fact, most cases of SA result from endocrinological disturbances impeding ovulation. In rare cases though, congenital or acquired uterine anomalies are the cause of SA [3].

Incidence rates of more than 5% have been reported for SA in the United States. While there don't seem to be racial influences on propensity for amenorrhea, dietary factors that, in turn, vary between geographic regions, do play an important role. This also applies for the prevalence of chronic diseases. In this context, increasing population shares suffering from obesity, diabetes mellitus and cardiovascular diseases, may serve as a possible explanation for the above mentioned high incidence of SA. The presence of hormonally active endocrine disruptors in the environment may differ greatly between distinct locations and may also trigger a variety of endocrinological disorders [4].

Of note, relations between dietary and environmental factors and onset of menstruation have also been proven for primary amenorrhea. In this line, the World Health Organization reported girls to experience menarche when aged 13 to 16 years, with significant differences between distinct countries.

As has been indicated above, the menstrual cycle depends on hypothalamic, pituitary and ovarial hormones. The hypothalamus releases gonadotropin-releasing hormone (GnRH) which stimulates production of pituitary gonadotropins FSH and luteinizing hormone (LH). Here, hormone release is regulated by means of negative feedback. This also applies for subordinate regulatory mechanisms.

FSH stimulates follicle growth and oocyte development and promotes the synthesis of estrogens by granulosa cells. Estrogens, in turn, stimulate endometrial thickening and thus help to prepare the uterus for implantation of a possibly fertilized egg.

An LH peak is required for ovulation. The oocyte leaves the follicle, is caught by the fallopian tube and may be fertilized. LH also triggers luteinization of theca cells and granulosa cells and therefore formation of the corpus luteum. Here, progesterone is produced and this hormone causes further remodelling processes, namely decidualization, of the endometrial layer of the uterus.

However, if the egg is not fertilized, estrogen and progesterone production decrease and the endometrium is no longer maintained in its ready-for-implantation state. In this case, parts of the uterine mucosa are discharged about two weeks after ovulation in form of menstruation bleeding.

This complex, multistage hormonal network has to work well on every level in order to ensure a physiological menstrual cycle. For menses to remain absent, this network may be disrupted at any level, e.g., at the level of pituitary gonadotropin release as in group I SA patients, at the level of the ovaries as in groups II and III as well as at the stage of cyclic endometrial changes.

Because dietary and environmental factors significantly affect reproductive health, a balanced diet, healthy body weight and avoidance of environmental toxins contribute to a physiological menstrual cycle.

In general, amenorrhea is the absence of menstruation [1]. While this is a physiological condition in girls who did not yet enter puberty, during pregnancy and in post-menopausal women, it as an abnormal state in any other woman in reproductive age. Whereas the failure of menses to occur in pubertal girls is termed primary amenorrhea, women whose menstruation ceases at later points in time are diagnosed with secondary amenorrhea (SA). Of note, regular menstrual cycles of intervals of more than five weeks are deemed oligomenorrhea.

In this context, a period of three months without menstruation bleeding justifies diagnosis of SA unless any of the aforementioned conditions is fulfilled. Some gynecologists diagnose SA before three months without menses have passed. Few women have very long menstrual cycles that may correspond to either oligomenorrhea or amenorrhea. The transition is smooth and while recommendations exist, there are no universally accepted definitions of those terms.

The most common cause of non-pathological SA is pregnancy and any patient presenting with SA should first be examined towards this end. Distinct endocrinological and ethological causes may account for pathological SA [2].

Secondary amenorrhea (SA) describes cessation of the menstrual period at any time during the reproductive age of a women. Amenorrhea merely refers to the absence of menses and is physiological in pre-pubertal girls, pregnant and post-menopausal women. Pathological SA does not correspond to any of these conditions but failure of menstruation to occur in any other situation.

It is to be noted that the most common cause for absence of menses is pregnancy.

Causes

Most cases of SA result from hormonal dysbalances that, in turn, may be caused by a variety of factors:

• Poor overall condition, e.g., obesity as well as extremely low body weight, chronical diseases such as celiac condition
• Behavioral disorders such as eating disorders or emotional stress
• Trauma, infection or tumors of the central nervous system, namely of hypothalamus or pituitary gland
• Polycystic ovary syndrome
• Premature ovary failure
• Follicle depletion
• Thyroid disorders
• Certain drugs, e.g., anti-psychotic medication and opioids
• Therapeutic interventions to treat uterine problems

Symptoms

While the main symptom of SA is absence of the menstrual bleeding for more than three months, additional symptoms may manifest according to the underlying disease. With regards to the above mentioned possible causes, an altered body weight, symptoms indicating systemic diseases, headaches, abdominal pain, painful menstruation and a variety of other problems may be experienced.

Diagnosis

The precise combination of symptoms helps to localize the cause of SA. After a pregnancy is ruled out, serum levels of sexual hormones such as follicle-stimulating hormone, prolactin and estrogen are assessed by means of blood samples. A thorough gynecologic examination will be complemented by transabdominal or transvaginal sonography.

The results of these exams may prompt further diagnostic measures.

Treatment

Treatment largely depends on the underlying disease and may comprise dietary adjustments, psychological therapy, treatment of endocrinological dysbalances and adaption of drug therapy prescribed for other diseases. Some conditions may require surgery.

Because low estrogen levels affect bone density, hormone replacement therapy may be indicated.

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3. Broome JD, Vancaillie TG. Fluoroscopically guided hysteroscopic division of adhesions in severe Asherman syndrome. Obstet Gynecol. 1999; 93(6):1041-1043.
4. Phillips KP, Foster WG. Key developments in endocrine disrupter research and human health. J Toxicol Environ Health B Crit Rev. 2008; 11(3-4):322-344.
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9. Bondy CA. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab. 2007; 92(1):10-25.