What Are the Most Common Amenorrhea Causes?

Amenorrhea (menorrhea) is an external manifestation of the pathophysiological changes in women caused by a variety of diseases. It is a clinical symptom and not a disease. According to the location of genital axis lesions and dysfunction, they are divided into hypothalamic amenorrhea, pituitary amenorrhea, ovarian amenorrhea, uterine amenorrhea, and abnormal genital amenorrhea. WHO has classified amenorrhea into 3 types: Type I: no endogenous estrogen production, normal or low follicle stimulating hormone (FSH) levels, normal prolactin (PRL) levels, and no evidence of hypothalamic or pituitary organic lesions Type II: Endogenous estrogen production, normal FSH and PRL levels; Type III: elevated FSH levels, suggesting ovarian failure

Basic Information

English name

amenorrhea

Visiting department

Gynecology

Common causes

Congenital developmental defects, such as vaginal atresia, ovarian dysplasia, etc.

Common symptoms

No menstrual cramps after a certain period of time

Amenorrhea clinical manifestations

(A) hypothalamic amenorrhea

Hypothalamic amenorrhea is amenorrhea caused by various functions of the hypothalamus and organic diseases. This type of amenorrhea is characterized by a deficiency or deficiency in the synthesis and secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus leading to the secretion of pituitary gonadotropin (Gn), which is the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH), especially LH Low function, so it belongs to low gonadotropin, low estrogen amenorrhea. According to the clinical cause, it can be divided into three categories: functional, genetic defect or organic, and drug.

Functional amenorrhea

This type of amenorrhea is caused by various stress factors that inhibit the secretion of hypothalamus GnRH, and the treatment can be reversed in time.

(1) The stress of amenorrhea and environmental changes can cause endogenous opioids, dopamine, and adrenocorticotropic hormone (ACTH) release hormone levels to increase stress, thereby inhibiting hypothalamus GnRH secretion.

(2) Amenorrhea can occur in athletes after continuous vigorous exercise. It is related to the psychological, stress response and decreased body fat of amenorrhea. Amenorrhea will occur if you lose 10% to 15% of your weight or lose 30% of your body fat.

(3) Amenorrhea caused by anorexia nervosa due to excessive dieting, leading to a sharp decline in body mass, eventually leading to a decrease in the secretion levels of various neuroendocrine hormones in the hypothalamus, causing secretion levels of various prohortic hormones, including LH, FSH, ACTH, etc. decline. Clinical manifestations include anorexia, extreme weight loss, low Gn amenorrhea, dry skin, hypothermia, hypotension, various blood cell counts, and low plasma protein levels, which can be life-threatening in severe cases.

(4) Nutrient-related amenorrhea, chronic wasting diseases, intestinal diseases, malnutrition, etc., leading to excessive decrease in body weight and weight loss can cause amenorrhea.

2. Genetic defects or organic amenorrhea

(1) Gene-defective amenorrhea A congenital defect in GnRH secretion caused by a gene defect. Kallmann syndrome with olfactory disorders and idiopathic low Gn amenorrhea without olfactory disorders. Kallmann syndrome is caused by a defect in the KAL-1 gene of chromosome Xp22.3, and idiopathic low Gn amenorrhea is caused by a mutation in the GnRH receptor 1 gene.

(2) Organic amenorrhea includes hypothalamic tumors, the most common of which is craniopharyngioma; there are still causes for inflammation, trauma, and chemotherapy.

3. Drug-induced amenorrhea

Long-term use of drugs that inhibit the central or hypothalamus, such as antipsychotics, antidepressants, contraceptives, metoclopramide (metolin), opiates, can inhibit the secretion of GnRH and cause amenorrhea, but generally after drug withdrawal Can restore menstruation.

(Two) pituitary amenorrhea

Pituitary amenorrhea is amenorrhea caused by a decrease in Gn secretion caused by pituitary lesions.

Pituitary tumor

Tumors can occur in various glandular cells in the pituitary gland located in the sphenoid saddle. The most common is adenoma that secretes PRL. The degree of amenorrhea is related to the degree of inhibition of GnRH secretion by the hypothalamus. If it occurs before puberty, it can cause primary amenorrhea. Depending on the nature of the tumor, clinically there may be symptoms unique to tumors such as galactorrhea, giant disease, and cortisol, and there may also be symptoms of nerve compression such as headache, visual impairment, and visual field defect.

2. Empty Sella Syndrome

Due to congenital hypoplasia of the saddle septum, or tumor and surgery to destroy the saddle septum, the subarachnoid space filled with cerebrospinal fluid extends to the pituitary fossa (saddle). Compression of the pituitary gland causes GnRH and dopamine secreted by the hypothalamus to pass through the pituitary portal circulation to the pituitary gland, which leads to amenorrhea, which can be accompanied by elevated PRL levels and galactorrhea.

3. Congenital pituitary lesions

Congenital pituitary lesions include diseases with a single Gn secretion function and pituitary growth hormone deficiency; the former may be caused by abnormal molecular structures of the and subunits of LH or FSH or abnormal receptors; the latter is caused by anterior pituitary Caused by insufficient leaf growth hormone secretion.

4.Sheehan syndrome

Sheehan syndrome is an acute infarction and necrosis of the pituitary due to postpartum hemorrhage and shock, which can cause hypopituitary dysfunction, resulting in hypotension, chills, lethargy, loss of appetite, anemia, weight loss, no lactation after delivery, Hair loss and low Gn amenorrhea.

(Three) ovarian amenorrhea

Ovarian amenorrhea is amenorrhea caused by the ovaries themselves. Gn levels increase during ovarian amenorrhea, and are divided into congenital gonadal dysgenesis, enzyme deficiency, ovarian resistance syndrome, and hypoovarian dysfunction caused by various causes.

Congenital hypogonadism

The gonads of the patient were strip-shaped, and were divided into two types of chromosomal abnormalities and normal chromosomes.

(1) Chromosome abnormality 45, X0 syndrome, karyotype 45, X0 and its chimera, such as 45, X0 / 46, XX or 45, X0 / 47, XXX, also 45, X0 / 46, XY Chimeric. 45. In addition to naive sexual characteristics, X0 women often have clinical features such as facial moles, short stature, webbed neck, shield chest, low posterior hairline, high ears, and elbow eversion, which are called Turner synthesis Sign.

(2) The normal chromosome karyotype is 46, XX or 46, XY. It is called XX or XY simple gonadal hypoplasia, which may be related to genetic defects. The patient has a female phenotype and has naive sexual characteristics.

2. Enzyme deficiency

Includes 17 hydroxylase or aromatase deficiency. There are many primordial follicles and presinus follicles and a small number of small sinus follicles in the ovary of the patient. However, due to the above-mentioned enzyme defects and estrogen synthesis disorders, hypoestrogenemia and FSH feedback increased; clinical manifestations are mostly Sexual amenorrhea and naive sexual characteristics.

3. Ovarian resistance syndrome

Patients' ovaries are not sensitive to Gn, also known as ovarian insensitivity syndrome. Gn receptor mutations may be one of the causes. Most of the ovaries are basal follicles and primary follicles, without follicular development and ovulation. Elevated endogenous Gn, especially FSH levels, may develop secondary sexual characteristics in women.

4. Premature ovarian failure

Premature ovarian failure (POF) refers to amenorrhea due to hypoovarian function in women before the age of 40, accompanied by symptoms of estrogen deficiency. Hormones are characterized by high Gn levels, especially elevated FSH levels, FSH> 40U / L, with decreased estrogen levels. Related to genetic factors, viral infections, autoimmune diseases, iatrogenic damage or idiopathic causes.

(IV) Amenorrhea due to uterine and lower reproductive tract development

Uterine amenorrhea

Uterine amenorrhea is divided into congenital and acquired. The causes of congenital amenorrhea include Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome and androgen insensitivity syndrome; the causes of acquired uterine amenorrhea include infection and trauma caused by intrauterine adhesions amenorrhea.

(1) MRKH syndrome In this type of patients, ovarian development, female reproductive hormone levels, and secondary sexual characteristics are completely normal, but the congenital absence of the uterus is caused by the unfused uterine segment formed by the bilateral paramedian renal ducts during the fetal period. Or the development of bilateral paramedian renal duct fusion ceased shortly after. The uterus is extremely small, without endometrium, and is often accompanied by urinary tract malformations.

(2) Patients with androgen insensitivity syndrome have a karyotype of 46, XY, and the gonads are dysplastic testes. Testosterone in blood is lower than normal males, but due to androgen receptor deficiency, males have abnormal internal and external genital differentiation. Androgen insensitivity syndrome is divided into two types: complete and incomplete. Complete androgen insensitivity syndrome is clinically manifested as female genitalia, with immature development and no pubic hair. Incomplete androgen insensitive syndrome may have axillary and pubic hair, but the sex of the external genitalia is unclear.

(3) Intrauterine adhesions usually occur after repeated abortions or after curettage, uterine infection or radiotherapy. Endometrial tuberculosis can also cause uterine adhesions to deform and shrink, eventually forming scar tissue and causing amenorrhea. Amenorrhea is caused by endometrial non-response and endometrial destruction during intrauterine adhesions.

2. Dysplastic amenorrhea of the lower reproductive tract

Dysmenorrhea of the lower genital tract includes cervical atresia, vaginal diaphragm, vaginal atresia, and hymen atresia. Cervical atresia can be caused by congenital dysplasia and adhesions after acquired cervical injury, often causing hemorrhage in the uterine cavity and fallopian tubes. The vaginal septum is caused by the incomplete or partial penetration of the tail end and the genitourinary sinus after the fusion of the paramedian renal ducts on both sides. It can be divided into complete vaginal septum and incomplete vaginal septum. Vaginal atresia is usually located in the lower part of the vagina. The upper 2/3 of the vaginal atresia is a normal vagina. Hymen atresia is caused by the failure of the urogenital sinus epithelium to penetrate the vestibular region, and amenorrhea due to the inability to discharge menstrual blood.

(V) Other

1. Diseases with elevated androgen levels

Including polycystic ovary syndrome (PCOS), congenital adrenal hyperplasia (CAH), androgen-secreting tumors, and follicular membrane cell proliferation.

(1) PCOS The basic characteristics of PCOS are ovulation disorder and hyperandrogenemia, which are often accompanied by polycystic ovarian changes and insulin resistance. The etiology of PCOS has not been fully identified. It is currently believed that this is a disease where genetic and environmental factors interact. Clinical manifestations often include symptoms of thin menstruation, amenorrhea and excessive androgen. Women of childbearing age are often accompanied by infertility.

(2) Androgen-secreting ovarian tumors are mainly ovarian stromal tumors, including ovarian stromal tumors, ovarian follicular membrane tumors, and so on. The clinical manifestations are obvious signs of hyperandrogenemia, which are progressively exacerbated.

(3) Follicular membrane cell proliferative disease Follicular membrane cell proliferative disease is the proliferation of ovarian mesenchymal cells-follicular membrane cells to produce androgens, which can show signs of virilization.

(4) CAH CAH is an autosomal recessive genetic disease. Common defects are 2l hydroxylase and 11 hydroxylase. Due to the lack of the above enzymes, the synthesis of cortisol is reduced, which increases ACTH reactivity, stimulates adrenal hyperplasia and adrenal glands. Increased synthetic androgens. Therefore, patients with severe congenital CAH can cause virilization of the external genitalia at birth. Mild onset of puberty may show signs and symptoms of hyperandrogenemia and amenorrhea similar to those in patients with PCOS.

2. Thyroid disease

Common thyroid diseases are Hashimoto's disease and toxic diffuse goiter (Graves disease). Often, autoimmune antibodies cause hypothyroidism or hyperthyroidism, and inhibit GnRH secretion to cause amenorrhea; it can also cause amenorrhea due to antibody cross-immunity to destroy ovarian tissue.
The classification and etiology of amenorrhea caused by lesions in different parts are shown in Table 1.

Amenorrhea diagnosis

Medical history

Includes a history of menstruation, a history of marriage and childbirth, a history of medication, a history of uterine surgery, a family history, and possible causes and accompanying symptoms such as environmental changes, mental trauma, emotional stress, sports occupations or excessive exercise, nutritional status, and headaches , Galactorrhea; those with primary amenorrhea should understand the process of pubertal growth and development.

2. check

Including physical examination, gynecological examination, hormone level determination, chromosome examination, imaging examination, basal body temperature measurement, hysteroscopy and so on.

3. Diagnosis process and differential diagnosis

The diagnostic process and differential diagnosis of primary and secondary amenorrhea are shown in Figures 1,2.

Amenorrhea

(A) physical examination

Includes intelligence, height, weight, development of secondary sexual characteristics, developmental abnormalities, goiter, breast galactorrhea, skin color and hair distribution. People with primary amenorrhea and naive sexual characteristics should also check for lack of smell.

(2) Gynecological examination

Internal and external genital development and whether there is malformation; married women can understand the level of estrogen in the body by examining the vagina and cervical mucus.

(Three) laboratory auxiliary inspection

Women with a history of sexual life who have amenorrhea must first rule out pregnancy.

1. Assess estrogen levels to determine the extent of amenorrhea

(1) Progesterone test: If there is bleeding after progesterone withdrawal, there is a certain level of endogenous estrogen in the body; if there is no withdrawal bleeding after discontinuation, there may be two cases: endogenous estrogen levels Low; amenorrhea caused by uterine lesions. The progestin test method is shown in Table 2.

(2) Estrogen-progesterone test Take an estrogen such as estradiol valerate or 17-estradiol or a combination of estrogen, and then add progestin after 20 to 30 days. The method of addition is shown in Table 2; Uterine amenorrhea can be ruled out for withdrawal bleeding; uterine amenorrhea can be determined for patients without withdrawal bleeding after discontinuation. However, if the medical history and gynecological examination have clearly identified uterine amenorrhea and abnormal genital amenorrhea, this step can be omitted.

2. Determination of hormone levels

It is recommended to stop estrogen and progesterone drugs for at least two weeks to determine hormone levels such as FSH, LH, PRL, and thyroid stimulating hormone (TSH) to assist diagnosis.

(1) Determination of PRL and TSH Blood PRL> 1.1nmol / L (25mg / L) was diagnosed as hyper PRLemia; PRL and TSH levels increased at the same time, indicating amenorrhea due to hypothyroidism.

(2) Measurement of FSH and LH FSH> 40U / L (measured more than 2 months apart), which indicates ovarian failure; FSH> 20U / L, which indicates hypoovarian function; LH <5U / L or normal range The lesion is in the hypothalamus or pituitary.

(3) Determination of other hormones Insulin, androgen (testosterone, dehydroepiandrosterone sulfate), progesterone, and 17-hydroxyprogesterone are required to determine whether obesity or clinical signs of hyperandrogenemia such as hairy, acne, etc. There are diseases such as insulin resistance, hyperandrogenemia or congenital 2l hydroxylase deficiency.

3. Chromosome inspection

Those with high Gn sexual amenorrhea and abnormal sexual differentiation should be examined for chromosomes.

(4) Other auxiliary inspections

Ultrasound examination

The presence of occupant lesions, uterine size, endometrial thickness, ovarian size, number of follicles and ovarian tumors.

2. Basal body temperature measurement

Learn about ovarian ovulation.

3. Hysteroscopy

Exclude intrauterine adhesions.

4.MRI or CT examination

Patients with headache, galactorrhea, or hyper PRLemia should undergo magnetic resonance (MRI) or CT examination of the skull and / or saddle to determine whether there are intracranial tumors and empty saddle syndrome, etc .; those with obvious virilization signs, Ovarian and adrenal ultrasound or MRI should also be performed to rule out tumors.

Amenorrhea treatment

Cause treatment

Some patients can recover menstruation after removing the cause. For patients with neurological and mental stress causes, effective psychological counseling should be performed; those with low body mass or amenorrhea caused by excessive dieting and weight loss should adjust their diet and strengthen nutrition; those with sports amenorrhea should appropriately reduce the amount of exercise and training intensity; Amenorrhea caused by hypothalamus (craniopharyngeal tumor), pituitary tumor (excluding tumors that secrete PRL), and ovarian tumors should be removed by surgery; high-Gn amenorrhea with Y chromosome, its gonads have malignant potential, and gonadal should be performed as soon as possible Resection; amenorrhea caused by dysmenorrhea due to abnormal drainage of menstrual blood, surgery should be corrected to make the menstrual blood flow smooth.

2. Estrogen and / or progestin treatment

Adolescence and amenorrhea caused by hypoestrogen in adults should be treated with estrogen. The medication principles are as follows:

(1) Promote bone growth For adolescent naive patients, when the height has not reached the expected height, the treatment should start from a small dose, such as 17-estradiol or estradiol valerate, or combined with estrogen; After height, the dose can be increased.

(2) Promote further development of sexual characteristics Adult amenorrhea with hypoestrogenemia first use 17-estradiol or estradiol valerate, or combine estrogen to promote and maintain general health and sexual development, waiting for uterine development Later, according to the degree of endometrial proliferation, progestin should be added regularly or sequential cycle therapy of estrogen and progestin should be used. Adolescent women's cycle therapy is recommended to use natural or near-natural progestins, such as dydrogesterone and micronized progesterone, which are beneficial to the recovery of reproductive axis function; patients with signs of excessive androgen can use anti-androgenic effects Progesterone formulations; for amenorrhea patients with a certain level of endogenous estrogen, regular progestin treatment should be used to make the endometrium fall off regularly.

3. Endocrine therapy for disease pathology and physiological disorders

According to the etiology of amenorrhea and its pathological and physiological mechanisms, targeted endocrine medications are used to correct hormone levels in the body to achieve therapeutic goals. For patients with CAH, long-term treatment with glucocorticoids should be used; for PCOS patients with obvious signs of hyperandrogenemia, oral contraceptives combined with estrogen and progestin can be used; for PCOS patients with insulin resistance, insulin sensitization can be selected Agent treatment. The above treatments can restore menstruation to patients, and some patients can resume ovulation.

4. Induced ovulation

For low-Gn amenorrhea, after estrogen therapy is used to promote the development of reproductive organs, and the endometrium has responded to estrogen and progesterone, urine gonadotropin (hMG) combined with human chorionic gonadotropin (hCG) Treatment, promote follicular development and induce ovulation. As it may cause ovarian hyperstimulation syndrome (OHSS), the use of Gn to induce ovulation must be administered by an experienced physician under conditions of B-ultrasound and hormone monitoring; for FSH and PRL With normal levels of amenorrhea, clomiphene citrate is preferred as an ovulation-promoting agent because of a certain level of endogenous estrogen in the patient's body. For amenorrhea patients with elevated FSH levels, due to their ovarian failure, it is not recommended Ovulation-promoting medication.

5. Assisted Fertility Treatment

For amenorrhea patients with fertility requirements, unsuccessful pregnancy after inducing ovulation, or problems with fallopian tubes, or infertility due to male factors can be treated with assisted reproduction technology.