I have my period again after three years of amenorrhea.

For female friends, menstruation is something they love and hate. Menstruation means that a woman's reproductive function is becoming more complete and she can give birth to and reproduce normally. If menstruation is abnormal, it may indicate that there is a problem with the reproductive system. Some women find that they have their periods again after three years of amenorrhea. What’s going on? This is most likely due to a physical disease that has caused amenorrhea. When this happens, it is important to check and treat it early.

Amenorrhea is an external manifestation of pathophysiological changes in the female body caused by a variety of diseases. It is a clinical symptom rather than a disease. According to the location of reproductive axis lesions and dysfunctions, it is divided into hypothalamic amenorrhea, pituitary amenorrhea, ovarian amenorrhea, uterine amenorrhea and amenorrhea due to lower reproductive tract developmental abnormalities. The World Health Organization classifies amenorrhea into three types: Type I: no endogenous estrogen production, normal or low follicle stimulating hormone (FSH) levels, normal prolactin (PRL) levels, and no evidence of organic hypothalamic and pituitary lesions; Type II: endogenous estrogen production, normal FSH and PRL levels; Type III: elevated FSH levels, indicating ovarian failure.

Amenorrhea can also be divided into primary and secondary, physiological and pathological. Primary amenorrhea refers to the age >14 years, the secondary sexual characteristics have not developed; or the age >16 years, the secondary sexual characteristics have developed, but the menstruation has not yet occurred. Secondary amenorrhea refers to the cessation of menstruation for more than 6 months after the normal menstrual cycle is established, or the cessation of the original menstrual cycle for more than 3 cycles. Physiological amenorrhea refers to the absence of menstruation during pregnancy, lactation and after menopause. Pathological amenorrhea is amenorrhea caused directly or indirectly by functional or organic lesions in various links of the central nervous system-hypothalamus-pituitary-ovarian axis and the target organ, the uterus.

1. Hypothalamic amenorrhea

Hypothalamic amenorrhea is amenorrhea caused by various functional and organic diseases of the hypothalamus. This type of amenorrhea is characterized by defective or insufficient synthesis and secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus, which leads to low secretion of pituitary gonadotropin (Gn), namely follicle-stimulating hormone (FSH) and luteinizing hormone (LH), especially LH, so it is a type of hypogonadotropic and hypoestrogenic amenorrhea. Clinically, the disease can be divided into three categories according to its cause: functional, genetic defect or organic, and drug-induced.

1. Functional amenorrhea

This type of amenorrhea is caused by various stress factors inhibiting the secretion of hypothalamic GnRH, which can be reversed with timely treatment.

(1) Stress-induced amenorrhea Mental shock, environmental changes, etc. can cause stress-induced increases in the levels of endogenous opioids, dopamine, and adrenocorticotropic hormone (ACTH)-releasing hormone, thereby inhibiting the secretion of GnRH in the hypothalamus.

(2) Sports-induced amenorrhea Athletes may experience amenorrhea after sustained strenuous exercise. It is related to the psychology, stress response level and body fat loss of amenorrhea patients. Amenorrhea will occur if the body weight is lost by 10% to 15%, or if the body fat is lost by 30%.

(3) Amenorrhea caused by anorexia nervosa is caused by excessive dieting, which leads to a sharp drop in body weight, eventually causing a decrease in the secretion levels of multiple neuroendocrine hormones in the hypothalamus, causing a decrease in the secretion levels of multiple trophic hormones in the anterior pituitary, including LH, FSH, ACTH, etc. The clinical manifestations include anorexia, extreme weight loss, low-Gn amenorrhea, dry skin, hypothermia, hypotension, low blood cell counts and plasma protein levels. Severe cases can be life-threatening.

(4) Nutrition-related amenorrhea Chronic wasting diseases, intestinal diseases, malnutrition, etc. that lead to excessive weight loss and emaciation can all cause amenorrhea.

2. Genetic defects or organic amenorrhea

(1) Genetic defect amenorrhea is a congenital GnRH secretion defect caused by a genetic defect. The main types are Kallmann syndrome with olfactory dysfunction and idiopathic low-Gn amenorrhea without olfactory dysfunction. Kallmann syndrome is caused by a defect in the KAL-1 gene on chromosome Xp22.3, and idiopathic hypogonadism is caused by a mutation in the GnRH receptor 1 gene.

(2) Organic amenorrhea includes hypothalamic tumors, the most common of which is craniopharyngioma; other causes include inflammation, trauma, chemotherapy, etc.

3. Drug-induced amenorrhea

Long-term use of drugs that inhibit the central nervous system or hypothalamus, such as antipsychotics, antidepressants, contraceptives, metoclopramide (Metoclopramide), opium, etc., can inhibit the secretion of GnRH and cause amenorrhea, but menstruation can generally resume after stopping the drug.

2. Pituitary amenorrhea

Pituitary amenorrhea is amenorrhea caused by decreased Gn secretion due to pituitary lesions.

1. Pituitary tumors

Tumors can occur in various glandular cells in the pituitary gland located in the sella turcica. The most common ones are adenomas that secrete PRL. The degree of amenorrhea is related to the degree of inhibition of PRL on hypothalamic GnRH secretion. If it occurs before puberty, it can cause primary amenorrhea. Depending on the nature of the tumor, clinical symptoms unique to the tumor may include galactorrhea, gigantism, hypercortisolism, etc., as well as symptoms of nerve compression such as headache, visual impairment, and visual field loss.

2. Empty sella syndrome

Due to congenital dysplasia of the sella turcica septum, or tumor or surgical destruction of the sella turcica septum, the subarachnoid space filled with cerebrospinal fluid extends to the pituitary fossa (sella turcica). Compression of the adenohypophysis blocks the transport of GnRH and dopamine secreted by the hypothalamus to the pituitary gland via the pituitary portal circulation, leading to amenorrhea, which may be accompanied by increased PRL levels and galactorrhea.

3. Congenital pituitary lesions

Congenital pituitary lesions include single Gn secretion dysfunction and pituitary growth hormone deficiency; the former may be caused by abnormal molecular structure of LH or FSH α, β subunits or abnormal receptors; the latter is caused by insufficient secretion of growth hormone from the anterior pituitary gland.

4. Sheehan syndrome

Sheehan syndrome is an acute infarction and necrosis of the pituitary gland caused by postpartum hemorrhage and shock, which can cause pituitary dysfunction, resulting in hypotension, chills, drowsiness, loss of appetite, anemia, weight loss, postpartum lack of lactation, hair loss and low-Gn amenorrhea.

3. Ovarian amenorrhea

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

1. Uterine amenorrhea

Uterine amenorrhea can be divided into congenital and acquired types. The causes of congenital uterine amenorrhea include Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome with müllerian duct malformations and androgen insensitivity syndrome; the causes of acquired uterine amenorrhea include amenorrhea caused by infection or trauma leading to intrauterine adhesions.

(1) MRKH syndrome: Patients with this syndrome have completely normal ovarian development, female reproductive hormone levels, and secondary sexual characteristics. However, due to the failure of fusion of the uterine segments formed by the bilateral paramesonephric ducts during the fetal period, they are congenitally without a uterus. Or the bilateral mesonephric ducts stop developing shortly after fusion. The uterus is extremely small, without endometrium, and is often accompanied by urinary tract malformations.

(2) The chromosome karyotype of patients with androgen insensitivity syndrome is 46,XY, and the gonads are dysplastic testicles. The testosterone level in the blood is lower than that of normal men, but due to the defect of androgen receptor, the male internal and external genitalia are abnormally differentiated. Androgen insensitivity syndrome is divided into complete and incomplete types. The clinical manifestations of complete androgen insensitivity syndrome are female-type external genitalia, immature development, and no pubic hair; incomplete androgen insensitivity syndrome may have axillary hair and pubic hair, but the gender of the external genitalia is unclear.

(3) Intrauterine adhesions usually occur after repeated artificial abortions or after curettage, intrauterine infection or radiotherapy. Endometrial tuberculosis can also cause adhesions, deformation, and shrinkage of the uterine cavity, and eventually form scar tissue, causing amenorrhea. Intrauterine adhesions may cause amenorrhea due to both endometrial unresponsiveness and endometrial destruction.

2. Amenorrhea due to dysplasia of the lower genital tract

Amenorrhea due to developmental abnormalities of the lower genital tract includes cervical atresia, vaginal septum, vaginal atresia and hymenal atresia. Cervical atresia can be caused by congenital developmental abnormalities and adhesions after acquired cervical injury, often causing blood accumulation in the uterine cavity and fallopian tubes. The vaginal septum is caused by the fusion of the two side mesonephric ducts, with the tail end of the duct not connected or partially connected to the urogenital sinus. It can be divided into complete vaginal septum and incomplete vaginal septum. Vaginal atresia is often located in the lower part of the vagina, while the upper 2/3 is a normal vagina. This is caused by the failure of the urogenital sinus to form the lower part of the vagina, and menstrual blood accumulates in the upper part of the vagina. Hymen occlusion is caused by the failure of the urogenital sinus epithelium to penetrate the vestibule, resulting in amenorrhea due to the inability of menstrual blood to be discharged.