Functional hypothalamic amenorrhea

　　1. Etiology

　　Refers to the disorder above the hypothalamus. Amenorrhea is caused by the lack or abnormal secretion of hypothalamic hormone GnRH. It includes abnormal function of the hypothalamus-pituitary unit, central nervous system-hypothalamus dysfunction, and amenorrhea caused by inappropriate feedback regulation of the hypothalamus due to other endocrine abnormalities.

　　2. Pathogenesis

　　1. Abnormal function of the hypothalamus-pituitary unit:The hypothalamus-pituitary dysfunction can be congenital, or secondary to damage, tumors, inflammation, and radiation, leading to hypothalamic hormone GnRH synthesis and secretion disorders. The most common menstrual disorders caused by hypothalamus-pituitary unit dysfunction in clinical practice are hyperprolactinemia. This is due to the lack of hypothalamic prolactin inhibitory factor (mainly dopamine), causing the pituitary to secrete excessive prolactin. In addition, any other cause that hinders the inhibition of prolactin secretion by dopamine can lead to hyperprolactinemia. For example, tumor compression of the pituitary stalk can block the inhibition of prolactin secretion by dopamine; certain drugs can increase prolactin secretion by consuming dopamine reserves or blocking dopamine receptor activity, such as metoclopramide and chlorpromazine. Other pituitary adenomas, hypothyroidism, nipple suckling, and chest stimulation can also cause an increase in prolactin secretion. Elevated prolactin levels can also act on the hypothalamus, inhibiting the synthesis and release of GnRH; acting on the pituitary, reducing the sensitivity of the pituitary to GnRH; and acting on the ovary, interfering with the synthesis of ovarian steroid hormones. In addition to amenorrhea, lactation is often one of the important manifestations of hyperprolactinemia. However, many patients cannot detect lactation themselves, and more than half are found during physical examination when seeking medical attention for amenorrhea or irregular menstruation. Laboratory tests will show elevated prolactin levels, >30ng/ml, FSH and LH levels equivalent to or lower than normal early follicular phase levels, and low estrogen levels. To exclude pituitary tumors, imaging examinations of the sellar region should be performed. If necessary, vision tests should also be conducted to be vigilant about field defects caused by tumor compression of the optic nerve.

　　2. Central-hypothalamic dysfunction:Psychological factors, changes in the external or internal environment, can lead to amenorrhea by affecting the hypothalamic function through the central nervous system, via the brain cortex, thalamus, and hypothalamus, or through the limbic system of the brain. In young women, typical situations such as sudden amenorrhea after psychological stress, emotional tension, or changing environments are more common. The levels of FSH, LH, and E2 can be within the normal range, but amenorrhea occurs due to the interference with the rhythm of GnRH pulse secretion, leading to anovulation. Anorexia nervosa, caused by deliberate weight loss and the pursuit of a slender figure, is not uncommon in adolescent girls. They may go from dieting to anorexia or develop peculiar eating habits, leading to severe weight loss, amenorrhea, and even dysfunction of multiple organs such as the thyroid, adrenal glands, reproductive glands, and pancreas, which can lead to water and electrolyte imbalances and extreme malnutrition, threatening life. Most of these patients can reveal a history related to psychological and mental factors. Generally, the levels of FSH, LH, and E2 are low. In addition, pseudopregnancy is also a central hypothalamic dysfunction caused by psychological and mental factors, commonly occurring in infertile women who are eager to have a child.

　　3. Other endocrine abnormalities cause inappropriate feedback regulation

　　(1) Excess androgens: Excess androgens can come from the ovaries and/or the adrenal glands. Clinically, polycystic ovary syndrome is the most common in adolescent girls. Its main pathophysiological characteristics are excess androgen levels and persistent anovulation, manifested as amenorrhea or menstrual irregularities, hirsutism, obesity, and a series of symptoms and signs such as polycystic enlargement of the ovaries. The main source of excess androgens is the ovaries, with some coming from the adrenal glands. The increased androgens are converted into estrogens in peripheral tissues. This continuous and non-cyclic estrogen conversion enhances the pituitary sensitivity to GnRH, leading to increased LH secretion and the loss of its cyclical nature, while FSH is relatively insufficient. The level of androgens in the blood circulation of patients with polycystic ovary syndrome is about 50% to 100% higher than that of normal women. If androgen levels are abnormally elevated, it is necessary to differentiate from other conditions, such as androgen-secreting tumors of the ovaries or adrenal glands, congenital adrenal cortical hyperplasia caused by enzyme defects, and other sexual development abnormalities.

　　Congenital adrenal hyperplasia is another common condition of excessive androgens in girls. It is due to the lack of a certain enzyme in the synthesis of steroid hormones by the adrenal cortex, resulting in excessive androgens, which interfere with the function of the hypothalamus-pituitary-gonadal axis and cause irregular menstruation or amenorrhea. In addition, patients often have varying degrees of masculinization or even genital malformation.

　　(2) Abnormal thyroid hormone: Thyroid hormones participate in the metabolism of various substances in the body. Therefore, both excessive and insufficient thyroid hormones can directly affect reproductive hormones and reproductive function, such as some hyperthyroid patients may show oligomenorrhea or amenorrhea.

　　(3) Secretory hormone tumors: Ovarian and adrenal tumors are common. Excessive secretion of sex hormones by tumors can inhibit the secretion regulatory function of the hypothalamus and pituitary through the feedback mechanism, disrupt its cyclicity, and lead to anovulation or amenorrhea. According to the characteristics of abnormally increased estrogen or androgen levels in the blood, the nature of the hormone secreted by the tumor can be judged. Detailed pelvic examination and imaging examinations of the corresponding sites, such as pelvic and adrenal B-ultrasound, CT scan, MRI, etc., are helpful for the diagnosis of tumors.

　　(4) Exercise and amenorrhea: Athletes, ballet dancers, and others who engage in high-intensity activities may experience exercise-induced amenorrhea due to low body fat. Energy expenditure, as well as the mental stress of training and competition, can affect neuroendocrine metabolic function, leading to abnormal secretion of GnRH in the hypothalamus, and causing amenorrhea.

　　(5) Drug-induced amenorrhea: Some drugs can affect hypothalamic function and cause amenorrhea, especially thiazide sedatives, which often cause amenorrhea and galactorrhea with high doses, and menstruation can recover after discontinuation. A few women may develop secondary amenorrhea after injection of long-acting contraceptive injections or long-term oral administration of high-dose contraceptives, which is caused by the sustained inhibition of the hypothalamus-pituitary axis by drugs.

　　(6) Obesity: Obesity sometimes is accompanied by other endocrine abnormalities. Here, it refers to simple obesity. Weight is closely related to the hypothalamus-pituitary-gonadal axis. Adipose tissue is a reservoir for estrogens and the main site for the extraglandular conversion of androgens to estrogens. Excessive adipose tissue leads to an increase in estrogens. This estrogen, generated without a cycle, exerts a continuous inhibition on the hypothalamus-pituitary through the feedback mechanism, leading to anovulation or amenorrhea.

　　Hypothalamic dysfunction can lead to abnormal secretion of various hormones, such as insulin deficiency leading to hypoglycemia; thyrotropin (TSH) deficiency leading to edema; adrenocorticotropic hormone (ACTH) deficiency presenting with signs similar to Addison's disease: hypoglycemia, hypothermia, bradycardia, susceptibility to infection, and shock. Other manifestations include secondary amenorrhea with weight loss, malnutrition. Even multiple systemic complications may occur, threatening life.

　　1. Amenorrhea due to mental factors

　　Patients of this type often have a history of mental stimulation, with only oligomenorrhea and amenorrhea, and may have infertility and weight loss. Relevant examinations show high blood cortisol levels, but without related clinical symptoms; the gonadotropin-releasing hormone stimulation test shows a pituitary response or delayed response to exogenous GnRH.

　　2. Pseudopregnancy

　　Patients may experience depression, amenorrhea, milk secretion, nausea and vomiting, decreased appetite, and other early pregnancy-like reactions when they desire to conceive. This is a typical neuroendocrine disease. When patients believe they are pregnant, a continuous high-temperature phase of BBT can be observed, with increased amplitude of PRL and LH secretion pulses in the blood, and E2 and P levels maintained at the luteal phase. However, when patients learn that they are not pregnant, the above hormone levels can drop sharply, followed by the resumption of menstruation.

　　3. Neurotic anorexia

　　Clinical manifestations: Common in adolescent or young women, aged 15-30 years, from middle and upper-class families, obsessed with a thin body shape, excessively restricting diet, triggering vomiting, and even almost not eating, significant weight loss, at least a 25% or more than 40% decrease in body weight compared to the original weight. Patients may have anorexia, refractory anorexia, or other symptoms of eating disorders, which may be accompanied by vomiting or abdominal bloating, abdominal pain, nausea, hiccups, and other abdominal symptoms. Complications may include esophagitis or ulcers, pancreatitis, etc. Commonly accompanied by dry skin, yellowing, hair loss, thinning hair, hypotension, low body temperature, constipation, and may also have diarrhea, aversion to cold, bradycardia, easy emotional excitation, introverted personality, depression, neurotic bulimia, or other neurological symptoms. Patients experience progressive weight loss, with the most prominent manifestation being amenorrhea (primary or secondary), accompanied by varying degrees of regression of sexual characteristics, sexual dysfunction, menstrual disorders, or complete amenorrhea. In addition to the above symptoms, there may also be urinary system, endocrine system, skeletal system, blood system, and metabolic complications, eventually presenting with severe cachexia.

　　4. Exercise-induced amenorrhea

　　This condition is common in female athletes. Due to long-term participation in intense sports training or competition activities, the hypothalamus-pituitary function becomes abnormal, causing delayed menarche or temporary menstrual disorders, leading to amenorrhea. The incidence of amenorrhea in long-distance runners can reach up to 59%, and ballet dancers up to 79%.

　　1. Enhance physical fitness, improve health levels, and strengthen physical exercise in daily life, often practice health exercises or Tai Chi, but avoid long-term intense sports.

　　2. Avoid emotional stimulation, stabilize emotions, and keep Qi and blood flowing smoothly. Pay attention to keeping warm during the menstrual period, especially below the waist, keep the feet warm, avoid cold water, and do not eat cold fruits and vegetables.

　　3. During the menstrual period, the body's resistance is weak, avoid heavy physical labor, pay attention to moderate work and rest, and coordinate the Qi and blood of the Chong and Ren meridians. Avoid cold and cool medicine during the menstrual period. Strengthen nutrition, pay attention to the spleen and stomach, and in good appetite, you can eat more meat, poultry eggs, milk, and fresh vegetables. Avoid spicy and stimulating foods.

　　4. Remove chronic lesions, avoid prolonged breastfeeding, be cautious in performing induced abortion, and correctly master the use of oral contraceptives. Obesity patients should appropriately limit dietary and salt intake.

　　5. In daily life, drinking tea not only prevents and improves amenorrhea but also regulates the balance of the human body's mechanism, enhances the body's resistance, and greatly reduces the recurrence rate of diseases. Herbs like purple herb, heart-leaf herb, medicinal Xianmao, and Xianlingpi have the effects of invigorating the Qi and nourishing the blood, anti-inflammatory and sterilization, clearing heat and dampness, removing unpleasant odors, and relieving itching.

　　1. Vaginal desquamated cell examination

　　This is a relatively common method to understand estrogen levels. Use a cotton swab soaked in physiological saline to take the desquamated cells from the upper segment of the vaginal lateral wall, spread them on a glass slide, fix and stain them, and then observe the percentage of cells in the superficial, middle, and basal layers. The higher the percentage of superficial cells, the higher the estrogen level reflects.

　　2. Cervical mucus

　　If the cervical mucus of amenorrheic patients is found to be transparent, thin, and elastic, and can be seen as fern-like crystals under a microscope after drying on a glass slide, it indicates that the patient's ovary has the function of secreting estrogen.

　　3. Drug tests

　　This is a commonly used clinical diagnostic test for amenorrhea, especially when there is a lack of hormone measurement equipment. Drug tests are very helpful in evaluating ovarian and endometrial function.

　　1. Progesterone test:For amenorrheic patients, apply progesterone intramuscularly at 20mg/d for 3-5 consecutive days; or medroxyprogesterone acetate 5-10mg/d for 5-7 consecutive days. Withdrawal bleeding occurs 3-7 days after discontinuation of medication (usually not more than 2 weeks). A positive test suggests: the endometrium is functional, which can exclude uterine amenorrhea; the ovary has the function of secreting estrogen, and the endometrium can respond to progesterone after being affected by a certain level of estrogen, indicating that amenorrhea is not due to a lack of estrogen, but due to various anovulatory causes of progesterone deficiency. If the progesterone test is negative, that is, there is no bleeding after discontinuation of medication, it suggests the following possibilities: one is hypofunction of the ovary, with no appropriate estrogen acting on the endometrium; two is normal ovarian function, but the endometrium has defects or damage and cannot respond to estrogen, which does not exclude uterine amenorrhea; three is not excluding pregnancy.

　　2. Estrogen test:For amenorrheic patients with negative progesterone tests, oral diethylstilbestrol 1mg/d, or ethinyl estradiol 10μg/d, or other estrogens with equivalent biological effects, for 20 consecutive days, adding progesterone 20mg/d by intramuscular injection in the last 3-5 days. Observe for withdrawal bleeding 3-7 days after discontinuation of medication. If there is still no bleeding, it suggests that the lesion may be in the uterus, that is, uterine amenorrhea. If there is withdrawal bleeding with the above test, it indicates that the endometrium responds to the effects of estrogen and progesterone and can undergo normal growth and shedding changes. The cause of amenorrhea should be in the ovary or higher, and further measurement of sex hormone levels should be carried out to confirm the diagnosis.

　　Determination of sex hormone levels

　　The determination of pituitary hormones is particularly important for diagnosing the cause of amenorrhea. For patients with amenorrhea and low estrogen levels, further determination of blood FSH, LH, and prolactin (PRL) levels is necessary. If FSH and LH levels are elevated, it suggests ovarian amenorrhea; if FSH and LH levels are low, the cause may be in the pituitary or hypothalamus; if FSH and LH levels are equivalent to normal follicular phase levels, amenorrhea is due to a disorder of hypothalamic secretion; if LH levels are elevated while FSH levels are relatively insufficient, polycystic ovary syndrome should be considered; if PRL levels are abnormally elevated, amenorrhea is caused by hyperprolactinemia, and further examination of the cause of hyperprolactinemia should be carried out, especially the possibility of a pituitary tumor should be noted.

　　When both FSH and LH levels are low, the pituitary stimulation test can further differentiate whether the lesion is in the pituitary or the hypothalamus. The pituitary stimulation test is to dissolve 100μg of LHRH in 5ml of normal saline, intravenously inject it within 30 seconds, and take blood to measure LH at 15, 30, 60, and 120 minutes before and after injection. If the LH value increases to more than 3 times the pre-injection level 30～60 minutes after injection, it indicates that the pituitary function is good, the hypothalamic hormone LHRH response is normal, and the cause of amenorrhea is in the hypothalamus or higher position. If the LH does not increase or increases slightly after injection, it indicates that the pituitary lacks response, and the cause of amenorrhea may be in the pituitary.

　　Fifth, basic body temperature measurement

　　It can indirectly understand the ovulatory function (see the gynecological endocrine examination method). After ovulation, the corpus luteum secretes progesterone, which has the effect of raising body temperature. The body temperature during the follicular phase of a normal menstrual cycle is relatively stable, generally fluctuating below 36.5℃, rising by 0.3～0.5℃ after ovulation, maintaining for 12～16 days, and dropping to the level of the follicular phase one day before or on the day of menstruation. This basic body temperature that is low in the first half of the cycle and high in the second half is called biphasic body temperature, which generally indicates the presence of ovulation or corpus luteum formation. Body temperature without this change is called monophasic body temperature, indicating no ovulation. The basic body temperature of amenorrheic patients is mostly monophasic, but due to normal ovarian function in uterine amenorrhea, it can show biphasic basic body temperature.

　　Pelvic ultrasound can assist in diagnosing the presence of congenital uterine agenesis or malformation, imaging examination of the sellar area can diagnose the presence of pituitary adenoma, diagnostic curettage, uterine iodine oil contrast and endoscopic examination can understand the uterine cavity and endometrial situation. In addition, if it is necessary to exclude other endocrine abnormalities or developmental malformations, the hormone levels of other related glands such as the thyroid and adrenal glands should also be checked, including biochemical, pathophysiological examination and karyotype examination, etc.

　　The diet and health care for patients with functional hypothalamic amenorrhea should pay attention to the following aspects:

　　1. Do not pursue thinness regardless of hunger and others' persuasion, refuse to eat, and cause hypokalemia, arrhythmia, and secondary amenorrhea.

　　2. Avoid long-term participation in intense sports training and overloading exercises.

　　3. Pay attention to a rich and balanced diet, regular life, which is conducive to the recovery of the body and the adjustment of the menstrual cycle.

　　First, treatment

　　Hypothalamic amenorrhea is one of the most complex types of amenorrhea, but generally speaking, it is also one of the best prognostic types. In addition to treating the corresponding primary disease, the following principles are adopted according to the patient's estrogen level and fertility requirements.

　　1. Those with fertility requirements should actively induce ovulation.There are several methods for induced ovulation:

　　(1) Clomiphene: It is commonly used for polycystic ovary syndrome and certain hypothalamic amenorrhea with a certain level of estrogen in the body. First, pregnancy hormones are used to induce bleeding, and then clomiphene 50-100mg/d is taken orally from the 5th day of bleeding for 5 consecutive days. Basal body temperature is measured to observe ovulation. Due to its low cost and simple usage, it is currently the most commonly used in clinical practice.

　　(2) Uroferrin (HMG): It is almost applicable to all types of hypothalamic amenorrhea.

　　(3) LHRH: This method is only suitable for patients with abnormal GnRH secretion in the hypothalamus but with normal responses from the pituitary and ovaries. The administration must simulate the physiological pulsatile secretion and release form of GnRH, and is administered intermittently as a pulse injection via intravenous, subcutaneous, or intramuscular routes, and can also be administered through nasal mucosa, anus, or vaginal routes, with intravenous administration being the most ideal. 5-20ug is injected every 90 minutes, and ovulation is monitored during administration.

　　(4) Bromocriptine: This drug is a dopamine agonist that acts on the hypothalamus, activates the prolactin inhibitory factor, inhibits the secretion of prolactin by the pituitary gland, and reduces the blood PRL level. The general dose is 5-7.5mg/d. Due to possible side effects such as orthostatic hypotension, nausea, vomiting, dizziness, constipation, etc., it should be started with a low dose and gradually increased slowly, and taken with food to greatly reduce side effects. Basal body temperature is measured during medication to monitor ovulation.

　　(5) Traditional Chinese Medicine: The treatment of hypothalamic amenorrhea with kidney deficiency and blood deficiency using Liu Fengwu's 'Four-Two-Five Combination Formula' in traditional Chinese medicine has a long history. For amenorrhea caused by blood deficiency and kidney deficiency, the formula includes four substances (Angelica sinensis, Rehmannia glutinosa, Paeonia lactiflora, and Polygonum cuspidatum), two Xian (Xianmao, Xianlingpi), and five seeds (Mucuna pruriens, Rubus chrysosporus, Lycium barbarum, Schisandra chinensis, and Plantago asiatica), which can achieve satisfactory therapeutic effects.

　　2. For hypothalamic amenorrhea with low estrogen levels and no desire for childbirth, the treatment is still mainly based on sex hormone supplementation; for unmarried individuals, when they need to have children after marriage, they can consider the above ovulation induction treatment accordingly.

　　II. Prognosis

　　Hypothalamic amenorrhea is the most complex type of amenorrhea, but it is also generally the one with the best prognosis. In addition to treating the corresponding primary causes, the above treatment principles are adopted according to the patient's estrogen level and whether they have a desire for childbirth.