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Pathophysiology, Diagnosis, and Treatment of Amenorrhoea

Amenorrhea is the absence of menstruation during the period of sexual maturity of a woman. Distinguish primary amenorrhea, if a girl to 16 years of age has never had menses. Secondary amenorrhea is observed in women who have previously ex-menstruation for some reason.

Pathophysiology of amenorrhea

Nevertheless, amenorrhea can also occur when ovulation takes place, as occurs with anatomical abnormalities of the genital organs, which create an obstacle to normal menstruation despite normal hormonal stimulation. It is customary to distinguish between physiological and pathological amenorrhea. Pathological amenorrhea – evidence of any disease: malformations of the sexual or cardiovascular systems, infantilism, neuropsychic disorders, upheavals, diseases of the endocrine system. Amenorrhea can be a consequence: tuberculosis of the genital organs, absence of an opening in the effective pleura, absence of the uterus or ovaries, and presence of scarring in the vagina. Amenorrhea is usually classified as anovulatory or ovulatory.

Amenorrhea sometimes does not cause women noticeable general health disorders, but in severe cases, unpleasant sensations are possible – hot flashes, nausea, dizziness, and depression. The clinical picture of amenorrhea is caused, as a rule, by a disease that causes the termination of menstruation. In the first place are the characteristic symptoms of developmental anomalies, infectious, endocrine, and other diseases, eating disorders, and intoxication. Amenorrhea in such cases is only a concomitant phenomenon, a consequence of the pathological processes inherent in the underlying disease. Quite often, the absence of menstruation leads to changes in metabolism, which causes obesity or, conversely, weight loss.

Diagnosis of amenorrhea

Girls are subject to inspection if:

  • they have no signs of puberty at the age of 13.
  • There is no pubic hair at the age of 14 years.
  • Menarche did not come before age 16 or two years after puberty began.

Women of reproductive age should be examined for pregnancy in the absence of menstruation for 1 month. It is necessary to undergo an examination for amenorrhea if the patient is not pregnant and she has no monthly for more than 3 months or 3 of their usual cycles; she has less than 9 menstruation per year; suddenly there are changes in the normal menstrual cycle. Anamnesis. Anamnesis of the present disease includes information about the presence of monthly (for the detection of primary or secondary amenorrhea); if there is menstruation, the age of menarche, the regularity of menstruation, the date of the last normal menstruation. It is also necessary to obtain information on the duration and intensity of menstruation, the presence or absence of premenstrual sensitivity of the breast, and mood changes in the growth, development, and age of the body.

The approach to examination with primary amenorrhea differs from that in secondary amenorrhea, although there are no generally accepted specific unified principles and algorithms. If the symptoms and signs make it possible to suspect a particular disease, a special examination can be shown, regardless of what is recommended by the algorithm. For example, if the patient has specific obesity of the trunk, face (“moon-shaped”), neck (“buffalo hump”), and thin limbs, it should be examined for the presence of Cushing’s syndrome. Patients suffering from headaches and violation of visual fields, or with signs of pituitary dysfunction, need an MRI of the brain.

A laboratory study of liver and kidney function determines ESR if a clinical examination suggests a chronic disease.

Often the examination includes determining the levels of hormones in the blood; the level of total testosterone or dehydroepiandrosterone sulfate (DGZAS) is determined only in the case of signs of virilization. To confirm the results, the levels of some hormones need to be re-examined. For example, if an increase in prolactin levels is found, repeat the study; if the level of FSH in the blood is increased, it should be measured monthly at least twice. Amenorrhea with an elevated level of FSH (hypogonadotropic hypogonadism) indicates a violation of the function of the ovaries.

If the patient with secondary amenorrhea does not have virilization, a normal prolactin level, FSH, and thyroid function are not compromised, a test with estrogens and progesterone challenge test can be performed to stimulate menstrual bleeding. The sample begins with a daily single oral intake of 5-10 mg of medroxyprogesterone or another progestin and lasts for 7-10 days.

  • The resulting bleeding indicates that amenorrhea probably is not a consequence of endometrial damage (for example, in Asherman’s syndrome) or an obstruction that violates the menstrual period, and its possible causes include hypothalamic-pituitary dysfunction, ovarian failure, or an elevated level of estrogen.
  • If bleeding does not occur, administer estrogen in a single dose daily for 21 days, followed by a daily oral medroxyprogesterone dose of 10 mg or another progestin for 7-10 days. If bleeding does not occur after taking estrogens, the patient may have endometrial damage.

However, bleeding may not be present in patients who do not have the abovementioned pathology (for example, because the uterus is not sensitive to estrogens). Therefore, a sample with estrogens and progestins can be repeated for confirmation. However, given that the trial lasts for weeks and the result may be inaccurate, the diagnosis of some serious violations can be significantly delayed. Therefore, an MRI of the brain should be performed before or during the test.

To diagnose many diseases, one of the symptoms of which is this condition, it is necessary to examine in a hospital. Only here are possible electroencephalography, diagnostic curettage of the uterus, X-ray examination, hysterography, hysteroscopy, etc. Endocrinology studies are performed in the hospital against the background of hormonal tests.

Treatment of amenorrhea

Treatment is directed at the underlying disease, which sometimes leads to the restoration of menstruation. For example, most conditions that create an obstacle to the admission of menstrual blood are correlated surgically.

In the presence of the Y chromosome due to the risk of the development of germicogenic cancer, removal of the ovaries (gonads) from both sides is recommended.

Problems associated with amenorrhea may, in turn, require treatment, including:

  • induction of ovulation with an interest in the onset of pregnancy;
  • treatment of manifestations of long-term estrogen deficiency (eg, osteoporosis);
  • treatment of long-term increase in estrogen levels (eg, prolonged bleeding, persistent and significant sensitivity of the mammary glands, hyperplasia, and endometrial cancer);
  • the greatest possible reduction in hirsutism and long-term exposure to elevated levels of androgens (such as cardiovascular disorders, and hypertension).

For the treatment of amenorrhoea, it is necessary to establish and eliminate the underlying cause, which causes the termination of menstrual function. A gynecologist must do this.

As a rule, the doctor takes measures to correct endocrine and metabolic disorders and treat diseases, the symptom of which is amenorrhea. After curing the main pathological process, the menstrual function is usually restored. Women also often require amenorrhea assistance from a psychologist and neuropathologist. With amenorrhea on the grounds of severe diseases, a doctor can prescribe hormonal drugs.

In women of reproductive age, the combination of estrogen with cycles of progestogen administration prevents the occurrence of chronic ovarian failure (osteoporosis, heart failure).

At the same time, there are general recommendations that should be remembered in the absence of menstruation: elimination of negative emotions and nervous breakdowns, rational nutrition, exercise therapy, climatotherapy, and regular outdoor walks. With primary amenorrhea and significant underdevelopment of the genitals, complex treatment is performed – general restorative drugs and hormone therapy are prescribed, and caloric nutrition is recommended.

Perhaps deep pawning with tinctures of marigold flowers and wormwood herbs. You can take alcohol tinctures of pharmacy from rhizomes of aira, ginseng, golden root, magnolia vine, and Eleutherococcus 20-30 drops once a day.

Violations of the menstrual cycle often occur in professional athletes, including those involved in running for marathon distances, gymnasts and figure skaters, and ballerinas. Depending on the type of activity and the level of competition, the frequency of amenorrhea varies from 5 to 25%. Violations of the menstrual cycle are more often recorded in women with lower body weight: ballerinas – 6-43%, engaged in jogging for medium and long-distance athletes – 24-26%.

Below is the frequency of violations in bicyclists (12%) and women swimming (12%).

In athletes with irregular menstruation, the pulsating LH surge is either characterized by a decreased frequency or occurs in the regime of transitional age. Heavy physical exercises lead to the hyperactivation of the hypothalamic-pituitary-adrenal system. However, the disturbance of the pulsatory rhythm of PH is not associated with stress caused by physical exertion, but rather with loss of energy.

Many of the athletes have a ” women’s sports triad “: amenorrhea, osteoporosis, and eating disorders.

Pronounced eating disorders, in particular bulimia and anorexia nervosa, disrupt menstrual function. Bulimia is characterized by alternating conditions: the absorption of large amounts of food in a short period of time (“shock food”), followed by artificially induced vomiting, the intake of laxatives or diuretics, and a restriction in diet. The incidence of bulimia varies from 4.5 to 18% among high school students and colleges and usually begins at the age of 17 to 25 years.

Anorexia nervosa is a serious eating disorder characterized by loss of body weight (more than 25% ideal), a violation of the perception of one’s own body, a constant fear of growing fat, and refusing to take measures to increase body weight. The total frequency of anorexia varies from 0.64 to 1.12 per 100,000. It is extremely important for the clinician to recognize the first signs of these disorders so that treatment can be prescribed promptly. Mortality from anorexia reaches 9%, and secondary cardiac arrhythmia develops due to electrolyte disorders and a decrease in muscle mass. Suicide attempts are comparatively frequent.

Anorexia nervosa is associated with a variety of neuroendocrine disorders. As a result of the decrease in caloric intake, the conversion of T4 to T3 decreases, resulting in a decrease in basal metabolism. T4 turns into an inactive isoform – reversible T3. Deep hypothalamic dysfunction manifests itself in hypothermia and reduced secretion of vasopressin, which can lead to partial diabetes insipidus, with a violation of the process of urine accumulation. As a result of hyperactivation of the hypothalamic-pituitary-adrenal system, hypersecretion of cortisol occurs, but manifestations of hypercorticism are rare because of a decrease in glucocorticoid receptor activity.

Bulimia and anorexia lead to a prepubertal type of LH secretion – the same as in patients with hypothalamic amenorrhea and presumably associated with a decrease in the secretion of luciferin. With increased body weight, normal LH secretion resumes in patients; the response to luciferin can be normal and exceed the norm despite normalizing body weight, in 50% of patients diagnosed with anovulation.

As with all states of energy deficiency, leptin plays a crucial role in disturbing hypothalamic function. Leptin is a protein hormone that is synthesized by fat tissue and plays an important role in adapting the organism to hunger. In leptin-deficient ob / on mice and leptin-resistant DB / DB mice, obesity and hypogonadotropic hypogonadism are observed. However, the crucial role of leptin is manifested when there is a lack of caloric content: it sends a signal to the brain about the energy deficit.

Thus, a reduced amount of leptin ” signals ” the hypothalamic-pituitary-adrenal system about energy deficiency. Leptin also plays a role in other neuroendocrine abnormalities, such as thyroid dysfunction and IGF-1 pathology, which are found in anorexia and other energy-deficient states in athletes.

The maiden’s membrane (KUTEL) sometimes does not have an opening due to disruption of the process of recanalization of the vaginal plate during the embryonic period and closes the entrance to the vagina, which blocks the exit of the menstrual blood. Such patients complain about the absence of menstruation and have a primary one. Over time, as a result of the accumulation of blood in the higher parts of the reproductive tract ( cryptomenorrhea ), the vagina (hematocolpos), and the uterus (hematoma) stretch, which is accompanied by abdominal or pelvic pain.

Diagnostics: An objective examination reveals an exaggerated maiden’s membrane, often of a purplish-red color due to hematocolpos. Surgical treatment consists of an arched opening of an unperforated maiden’s membrane.

The transverse membrane of the vagina

The transverse vaginal membrane can arise as a result of the embryonic fusion of the upper part of the vagina, which is of Müller origin, with the lower part that comes from the urogenital sinus. The membrane is usually located in the upper half or middle of the vagina. Sometimes, this membrane can be unperforated, which causes the primary (cryptomenorrhea), as in the case of an unperforated maiden’s membrane.

Diagnostics: The diagnosis is based on a thorough objective examination of the reproductive tract. The transverse membrane of the vagina is often mistaken for an unperforated maiden’s vestibule. With an imperforate maiden’s membrane, unlike the transverse vaginal membrane, a hymen ring is found below the membrane.

Testicular feminization

Testicular feminization is a congenital insensitivity to the action of androgens due to dysfunction or lack of testosterone receptors, which leads to the formation of a female phenotype in individuals of genetic males (46, X ¥). The frequency of this syndrome is 1:50 000 women. Due to the presence of testicular tissue (testicles), from the early stages of development, the Mullerian inhibitory factor is secreted, hence, such individuals do not have structures of Müller’s origin. The testicles may not be emptied or migrate into the large labia. The decrease or lack of sensitivity to testosterone leads to the absence of pubic and axillary hair. The production of estrogens usually takes place, which leads to the development of mammary glands, but the absence of the uterus is accompanied by primary amenorrhea. Such patients often have a vagina in the form of a blind pocket.

Reconstructive surgical treatment includes the creation of neovagina for the possibility of sexual function. Reproductive function in such patients is absent.

Slayer syndrome congenital absence of testicles in persons of genetic males – leads to the development of a female phenotype, like ovarian agenesis. Due to the lack of development of the testicles, the MYTH is not excreted, and these patients have internal and external female genitalia. However, the lack of estrogen production leads to the lack or insufficient development of mammary glands.

Pathogenesis – The causes of this disease are not fully established, but with the development of the disease, a vicious circle of ovarian function is established. Chronic anovulation leads to an increase in the level of estrogens and androgens. A growing number of androgenic ovarian and adrenal origin are subject to peripheral conversion in adipose tissue to estrone. Later, the increase in the level of androgens leads to a decrease in the production of globulin, which binds sex steroids, which, in turn, further increases the level of estrogens and androgens. This hyperestrogenic condition leads to an increase in the level of LH / FSH, atypical follicle development, anovulation, and an increase in the production of androgens. So, again, androgens in the periphery are converted into estrone, leading to the disease’s clinical progression.

Many patients with polycystic ovary syndrome and concomitant hyperandrogenism and obesity develop insulin resistance and hyperinsulinemia, which can lead to the development of type II diabetes mellitus (non-insulin-dependent diabetes mellitus).

Clinic. Increasing the secretion of androgens and reducing the level of globulin, binding sex steroids, leads to an increase in the level of free testosterone, which reaches the target cells in the skin and hair follicles. This causes the development of hirsutism – excess hair in the androgen-sensitive areas: the face, the upper half of the back, the chest, the lower half of the abdomen, and the inner thighs.

A characteristic feature of skin manifestations of hyperandrogenemia is acanthosis – the appearance of gray-brown velvety hyperpigmented zones on the skin of the back of the neck, in the axillary zones and skin folds; Acanthosis is often associated with hyperinsulinemia.

The pathognomonic symptom of PCOS is chronic anovulation, which increases the risk of endometrial cancer to 3-5%. Manifestations of chronic anovulation in patients with PCOS are usually oligomenorrhea and dysfunctional (anovulatory) uterine bleeding.

Hypertriglyceridemia and a decrease in the level of high-density lipoproteins increase the risk of cardiovascular diseases by 2-7 times and cerebrovascular diseases by 3 times. Therefore, the lipid profile control in patients with PCOS should be performed every 3-5 years after 35 years. Abnormal glucose metabolism and hyperinsulinemia with a decrease in insulin sensitivity increase the incidence of obesity and type II diabetes mellitus (risk 25-35% to 30 years) in such patients.

Diagnostics. The main criteria for diagnosing PCOS are:

1) hyperandrogenemia with (or without) dermal manifestation;

2) chronic anovulation;

3) signs of PCOS during ultrasound examination;

4) absence of other hyperandrogenic disorders and hyperprolactinemia.

The main laboratory confirmations of PCOS syndrome are:

1) increased levels of testosterone and androstenedione (due to LH-stimulation of stromal and thetical production and a decrease in FSH-induced aromatization of androgens in estrogens in granulosa cells);

2) an increase in the production of estrone due to aromatization of androstenedione in estrone in adipose tissue (which leads to a decrease in FSH level and growth of LH behind feedback);

3) increased levels of DHEA and DHEAS (in 50% of patients with PCOS, 95% of DHEAS is produced by the adrenal glands);

4) often increase the ratio of LH / FSH> 3: 1;

5) hyperinsulinemia. Hyperinsulinemia promotes the growth of androgen production by the ovaries and a decrease in the level of globulin that binds sex steroids;

6) low or normal level of FSH;

7) decrease in the level of globulin, binding sex steroids, which contributes to hyperandrogenism and obesity;

8) low level of estradiol.

Differential diagnosis of PCOS is carried out with such syndromes as:

  • hyperprolactinemia;
  • adrenal hyperplasia with onset in adulthood;
  • tumors of the ovaries and adrenal glands;
  • Cushing’s syndrome.

These states are excluded by examining such tests:

1) serum prolactin level;

2) the level of 17-hydroxyprogesterone;

3) serum testosterone level (increased in ovarian and adrenal tumors);

4) dehydroepiandrosterone sulfate (DHEAS);

5) Conduct a suppressor test with 1 mg dexamethasone (at night).

Ultrasound PCOS criteria may include various signs that vary in different patients: bilateral ovarian enlargement (not always), the presence of a dense ovarian capsule, subcapsular follicular cysts or follicles (8-10) with a diameter of about 10 mm (a “necklace” symptom), etc.

Treatment of patients with PCOS depends on the symptoms of the disease and reproductive intentions.

For patients who are ready for pregnancy, treatment usually begins with the use of clomiphene-citrate (klostilbegita) to induce ovulation. Clomiphene is prescribed at 50-150 mg/day, usually from the 5th to the 9th day of the menstrual cycle. The course of treatment usually does not exceed 3-6 cycles. During the application of clomiphene, the choice of the optimal dose of the drug should be monitored through tests of functional diagnostics (quality of cervical mucus, basal body temperature, pupil symptom, “fern leaf”) and ultrasound folliculometry to identify the dominant follicle and signs of ovulation. The frequency of achieving ovulation with clomiphene is 80%, the frequency of pregnancy is 40-50%.


Bacopoulou, F., Creatsas, G., Chrousos, G. P., Papanikolaou, N., & Deligeoroglou, E. (2014). Primary amenorrhea in adolescent girls: normal coitus or not? Always take a look in the physician’s office. BMC Women’s Health, 14(1), 1-10. doi:10.1186/1472-6874-14-23

Bal, H., Sharma, S., Ali, I., & Ashtekar, A. (2016). A rare case of primary amenorrhea. Medical Journal Of Dr. D.Y. Patil University, 9(2), 237-240. doi:10.4103/0975-2870.177674

Berz, K., & McCambridge, T. (2016). Amenorrhea in the Female Athlete: What to Do and When to Worry. Pediatric Annals, 45(3), e97-e102. doi:10.3928/00904481-20160210-03

Klein, D. A., & Poth, M. A. (2013). Amenorrhea: an approach to diagnosis and management. American Family Physician, 87(11), 781-788.

Pereira, K., & Brown, A. J. (2017). Secondary amenorrhea: Diagnostic approach and treatment considerations. Nurse Practitioner, 42(9), 34-41. doi:10.1097/01.NPR.0000520832.14406.76



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