Dysfunctional uterine bleeding (referred to as gonorrhea) is one of the most common diseases affecting women’s health. The most serious danger is the series of complications caused by bleeding, followed by the impact of irregular bleeding on women’s quality of life and physical and mental health. Therefore, the primary goal of treatment for gonorrhea is to stop bleeding to avoid anemia and shock caused by massive blood loss, and even life-threatening; the second is to adjust the menstrual cycle to avoid recurrence of bleeding.
1.Various methods of medication and their principles
The main cause of menorrhagia is the dysfunction of the hypothalamic-pituitary-ovarian axis, especially in patients with anovulatory menorrhagia, because of the absence of progesterone secretion, the endometrium cannot change in the secretory phase, and the uterus cannot close the small spiral arteries by normal contraction, resulting in bleeding. Therefore, theoretically, if the endometrium can be completely shed or repaired, the hemorrhage can be stopped.
The usual measures to stop bleeding with sex hormones can be summarized in the following three categories:
(1) Endometrial shedding: the endometrium is completely shed and the hemorrhage is stopped by normal contractions that close the small spiral arteries
(2) Endometrial repair method: the endometrium is partially shed and repaired to stop bleeding.
(3) Endometrial atrophy method: to stop the bleeding by shrinking and thinning the unexfoliated endometrium.
The sex hormone therapy that can perform the above measures is accordingly:
(1) Progestin therapy is used to cause complete secretory phase changes in the endometrium, and the bleeding is stopped when the endometrium is completely shed after stopping the drug.
(2) Using a large amount of estrogen to make the endometrium grow rapidly and repair the area where the endometrium has been shed, so as to stop the bleeding.
(3) Application of large doses of progestin to make the endometrium shrink and thin in a short period of time to stop bleeding.
2.The indications and clinical application characteristics of various therapies
The selection of the above therapies under different circumstances depends on the patient’s hemoglobin (Hb) level, the type of gonorrhea, the availability of various sex hormone preparations, the patient’s responsiveness, and other combined conditions, etc., of which the first two are key factors. First of all, the level of hemoglobin determines the risk of further blood loss. If the Hb value is below 70g/L, the patient has reached the level of severe anemia, and further blood loss will cause life-threatening consequences. In contrast, Hb80~100g/L is moderate anemia, and there are no obvious signs of blood loss, so the endothelium can be allowed to shed after short-term medication (5~7d) to achieve hemostasis.
For patients with Hb of 70~<80g/L, the method of hemostasis should be determined according to the general condition, if the general condition is poor and bleeding is obvious, rapid hemostasis is recommended, while for patients with good general condition and little bleeding, the endothelial shedding method can be applied. patients with Hb>100g/L basically have no signs of blood loss, and endothelial shedding method is mostly recommended. However, for patients with long-term irregular menstruation combined with blood disorders or immune system diseases, endometrial atrophy is recommended to reduce menstrual flow and adjust menstruation or amenorrhea.
The former is often the main cause of moderate to severe anemia, while the latter is usually free of anemia and only manifests itself as a small amount of bleeding at a certain time of the menstrual cycle. Therefore, this article will focus on anovulatory type of eclampsia.
Anovulatory eclampsia occurs mainly during two periods in women: adolescence and the menopausal transition. The following methods are used for the definitive diagnosis of eclampsia (with the exception of hematologic, immunologic, and tumorigenic factors), depending on the hemoglobin level, and the specific applications of the three methods are as follows.
2.1 Endometrial shedding method The common preparation is progesterone for intramuscular injection, 20mg each, usually used once a day for 3 d. However, in clinical practice, due to the short duration of action of progesterone, the endometrial secretion phase is not completely transformed, and the amount of retreat bleeding is high, androgen (e.g. testosterone propionate 25mg, qd×3d) should be added at the same time. In the author’s experience, it can be extended to 5~7d, because after the use of progestin, the bleeding of the patient will soon be significantly reduced or completely stopped, and the use of slightly longer time can further increase the hemoglobin level of the patient and reduce the problems caused by blood loss.
However, progestins should not be used for long periods of time, as they may cause rebleeding. If prolonged use is needed, the dose of progestin should be increased several times, and the effect is the same as the endometrial atrophy method. In addition, oral preparations can be used, such as medroxyprogesterone acetate (trade name progesterone) 6~8mg/d for 7~10d, or the natural progestin Daphne 10mg, bid for 7~10d. Other oral preparations are similar.
If there is no significant change or increase in bleeding, pregnancy should be excluded firstly; secondly, endometrial lesions such as endometrial cancer, atypical hyperplasia, submucosal fibroids or polyps and cervical factors should be considered. Withdrawal bleeding usually occurs 2-4 d after stopping progesterone and ends in about 7 d. If the withdrawal bleeding does not stop in more than 10 d, the patient may have to go to the hospital. If the withdrawal bleeding does not end in more than 10 d, careful gynecological examination and endometrial biopsy should be performed, with emphasis on excluding endometrial lesions, such as cancer or atypical hyperplasia.
2.2 Endometrial repair method The commonly used estrogen preparation is estradiol benzoate, which is injected intramuscularly at 1mg each, the starting dose starts at 2mg, and the bleeding is observed within 4h after application. If the bleeding is completely stopped at 4h, the second dose of 2mg of estradiol benzoate can be given until 6h or 8h until there are signs of bleeding again, and the bleeding is observed in the same way until the total dose is calculated at 24h. mg, q6h, but at most one dose reduction should not exceed 1/3 of the total 24h dose, and then maintain the dose for 3 d, and so on, until Hb≥100g/L, and progestin can be added for 5~7d to retreat bleeding. There is no need to reduce the dose to 1mg/d or to maintain it for as long as possible before stopping it. Sometimes, for clinical convenience, estradiol benzoate 2mg can be given empirically for q4h or q6h to achieve hemostasis within 24h. In some areas, estradiol benzoate injections are not available, so oral medications are used instead.
In some areas, estradiol benzoate injections are not available, so oral medication can be used instead. However, the metabolic characteristics of oral estrogens determine the instability of the blood concentration, and the hemostatic effect is slightly less effective. Oral preparations that can be used in clinical practice, such as Bemelia tablets, are 0-625mg per tablet, and the starting dose starts with 2-4 tablets, which can also be given once in 4, 6 or 8 hours. Other natural estrogen preparations such as estradiol valerate (1mg per tablet) and 17-beta estradiol (1mg per tablet) can be used in the same way as above. Oral administration is convenient and easily accepted by patients.
Problems to be noted in drug application:
(1) The basic condition to ensure the effectiveness of this therapy is normal coagulation function. Therefore, it is necessary to exclude hematologic diseases before starting the drug. It should be emphasized that for patients with Hb<50g/L, poor general condition and recent bleeding, even if they do not have hematologic diseases, the loss of a large amount of clotting factors due to blood loss may cause abnormalities in the clotting mechanism. (2) For estrogen benzoate
(2) If the dose of estradiol benzoate has reached 12mg/24h and the bleeding has not been effectively stopped in 48-72h, it is necessary to repeatedly check for hematologic disorders such as occult platelet anemia, or to exclude other gynecologic disorders causing bleeding such as submucosal myoma or polyps, or even the possibility of pregnancy.
(3) When hemostasis has been achieved and the dose of estrogen has not changed, but there is recurrent bleeding, it is necessary to check whether there is a possibility of drug leakage during intramuscular injection (because estradiol benzoate injection is an oil, it is difficult to push it intramuscularly).
(4) After stopping the bleeding, reduce the dosage by no more than 1/3 of the total amount of the previous 24 h. Otherwise, it will easily cause rebleeding, and if it bleeds again, the original dosage should be restored.
2.3 Endometrial atrophy method is usually used to stop bleeding by atrophying the endometrium with high efficiency or high dose of progestin. Commonly used preparations include 18-methylnortriptyline, or levonorgestrel, etc. However, few of the above preparations are available in the market at present, and Yutin (an emergency contraceptive containing levonorgestrel 0-75mg) is sometimes used in clinical practice. There is no unified view on how to reduce the dose, but the experience of Peking Union Medical College Hospital is that the dose of progestin (Yutin) can be reduced to 1 tablet for maintenance until the hemoglobin level reaches 100g/L, and then the drug is stopped and withdrawn. In this case, the amount of withdrawal bleeding is usually low after discontinuation. In addition, the optional preparations include medroxyprogesterone acetate or norethindrone acetate, etc. If the dose is increased several times, such as medroxyprogesterone acetate, the recommended dosage is 30-60mg/d, and the method of reducing the dosage after stopping bleeding is the same as above. The main problems in application:
(1) The endometrial atrophy method is usually recommended for women in the menopausal transition or for patients with combined immune system diseases, such as lupus erythematosus, and rarely for women in adolescence or childbearing age. It is rarely used in adolescent or childbearing women, as some patients may experience decreased menstrual flow or even amenorrhea in rare cases.
(2) Liver function should be monitored during treatment to avoid liver damage.
3. Application of other sex hormone preparations
The main purpose is to constrict blood vessels and reduce bleeding, but the use of androgens alone cannot achieve the purpose of hemostasis. Testosterone propionate is generally used in the form of 25mg or 50mg per dose, and the dosage should not exceed 300mg per week (within 1 month), divided into 3 days. Adolescent girls are generally given 25mg/d for 3 d. The dose can be increased for women in the menopausal transition.
3.2 The use of new contraceptive pills In addition to the control of menstrual cycle, some doctors now use contraceptive pills for the hemostatic treatment of menstrual bleeding. The two new contraceptive pills currently in use, mafron and mydrium, both contain 35 μg of ethinyl estradiol, but contain the highly effective progestins disoproxil and progesterone, respectively. Because of their high potency, they can achieve some of the effects similar to those seen in endometrial atrophy. Moreover, low doses of estrogen induce the production of progesterone receptors, enhancing the effect of progesterone.
The principle of clinical use is partly similar to that of endometrial atrophy, which reduces menstrual flow but does not cause amenorrhea. There is no consensus in China on how to apply it. The author’s experience is that for patients with hemoglobin level above 60g/L, the starting dose should be 2~4 tablets each time, given at q4h or 6~8h, and the hemorrhage usually stops within 48~72h, and then maintained for 3 d. The dosage reduction pattern is similar to that of estrogen in the endometrial repair method.
The dose reduction pattern was similar to that of estrogen in endothelial repair. After the hemoglobin level rises to 100 g/L, the drug is discontinued.
The endometrial detachment method was given without checking the hemoglobin level. If the patient’s Hb≥80g/L, the withdrawal bleeding will not cause serious effects; however, if the patient’s Hb<70g/L, especially those whose hemoglobin level is already very low (around 50g/L), the hemoglobin may decrease by 20~30g/L after one progestogen withdrawal bleeding, which may further aggravate the condition of the patient who is already severely anemic. What is the further treatment? It is inappropriate to add estrogen therapy (because the endometrium is already in the secretory phase of change). The appropriate option is to give supportive therapy, such as blood transfusion, rehydration and electrolyte balance. Since withdrawal bleeding usually stops within 7 days (2-4 days in case of high volume).
Before applying the endothelial shedding method, it is necessary to explain to patients and their families that they can bleed again after stopping the medication. However, sometimes patients ask doctors to stop bleeding again due to fear, or some doctors do not understand this method and repeatedly use the progestin shedding method, resulting in repeated bleeding and stopping bleeding, which eventually leads to extremely low hemoglobin levels and cannot be treated. After hemostasis is complete, the importance of further treatment needs to be emphasized with the patient and family, with the main aim of preventing the recurrence of gonorrhea. Follow-up treatment is to adjust the menstrual cycle to basic regularity.
Specific methods:
(1) Progestin for regular withdrawal of bleeding.
(2) Contraceptive pills to control the menstrual cycle.
(3) For patients with fertility requirements, ovulation is induced and the cycle is adjusted.
The pathogenesis of menopausal transition is similar to that of adolescence, but there are differences in clinical management. Because of the possibility of organic lesions in the transitional menopause, endometrial repair is generally used sparingly and replaced by diagnostic curettage. If the patient’s hemoglobin is <70g/L, diagnostic curettage is recommended; if the hemoglobin is >80g/L, progesterone endometrial detachment is recommended. In addition, for patients with menopausal transition, the endometrial atrophy method can be used, and the indications for selection are as described above.
4.Management of ovulatory type of eclampsia
Ovulatory type of meritorious hemorrhage mainly includes 3 types:
(1) Luteal insufficiency.
(2) Luteal atrophy insufficiency.
(3) Ovulatory bleeding. There is no unified treatment for these 3 types of ovulatory type of meritorious hemorrhage. Most of them are treated with estrogen, progestin, combined estrogen and progestin or contraceptive pills. The efficacy of treatment varies greatly among individuals.
4.1 Luteal insufficiency The main effect on women is the inconvenience and psychological burden caused by the small amount of bleeding before menstruation. Therefore, the main treatment goal is to eliminate the small amount of premenstrual bleeding caused by low progesterone levels, and theoretically the missing part of progesterone should be replaced. One of the commonly used clinical methods is to give the right amount of progestin in the middle and late luteal phase, usually using medroxyprogesterone acetate, which is given at 4-8mg/d for about 10d, and the menstruation will come after stopping the medication; or using Daphne 10mg, Bid can also be used. However, other people have tried to use contraceptive pills or estrogen and progestin combination given by artificial cycle. The dosing method follows the instructions for conventional short-acting contraceptives (e.g., Mafron, Mendocino, etc.). Artificial cycle
Estrogen (e.g., Bemelia 0-625 mg/d, Glaxo 1~2 mg/d) can be given for 21~28 d, followed by progestin (medroxyprogesterone acetate 4~6 mg/d or Duffetone 20 mg/d) for 10~14 d. Other methods include clomiphene, which is used in the same way as ovulation treatment (50mg/d on the 1st-5th day of menstruation for 5 d).
4.2 Luteal atrophy The main effect is the discomfort of life and psychological discomfort of women due to small amount of bleeding after normal menstruation. The aim of treatment is to eliminate the bleeding caused by incomplete shedding of the endometrium due to low levels of progesterone after menstruation. Theoretically, the bleeding can be stopped if the endometrium is repaired as soon as possible and the small ruptured blood vessels are closed. Therefore, the common method is to add a small amount of estrogen to accelerate the growth and repair of the endometrium. This is usually done from the early follicular phase (around the 5th day of menstruation), e.g., 0.3~0.625mg/d of Bemelia or 1-2mg/d of Tegretol, and stopping for 10~15 days. Other methods include progestin-only therapy, contraceptive pills, combined estrogen and progestin therapy, etc. The administration is the same as that in luteal insufficiency.
4.3 Ovulatory bleeding A few women may experience bleeding visible to the naked eye during ovulation. Although the amount is small, the patient is under psychological stress or fear, and if there is a requirement for treatment, clinical management is required, otherwise observation can be made. The main cause is the instability of the endometrium due to the marked changes in the levels of various hormones after ovulation. Theoretically, the problem can be solved with the addition of estrogen or progestin. It may be thought that since the problem is caused by ovulation, it can be treated by using contraceptives to prevent ovulation.
However, the pill itself can cause a small amount of irregular bleeding during the first 3 months of use and should be explained to the patient before use. Oestrogen therapy alone is usually given in small doses (e.g., Bemelia 0-3 mg/d, Tegretol 1 mg/d) starting from the early follicular phase for 14-22 d. The main purpose is to stabilize the endometrial changes caused by changes in hormone levels during ovulation. The duration of use can be stopped after ovulation or continued until premenstruation. Progestin alone is usually started 3-5 d before ovulation and lasts for 10-15 d.
As mentioned above, the main risk of miscarriage is the different degrees of complications caused by bleeding at different times and in different amounts, which can be life-threatening in the most serious cases. The primary goal of treatment is to stop bleeding in order to avoid serious complications. The second is to prevent rebleeding by adjusting the menstrual cycle. There are three main types of sex hormone therapy: endometrial shedding, endometrial repair and endometrial atrophy.
The hormones commonly used are estrogens, progestins and androgens, as well as steroid hormone preparations containing these components. The key factors in the selection of different therapies are the hemoglobin level and the type of hematoma. Properly applied, satisfactory clinical results can be achieved. However, if conventional treatment is not effective, further investigations are needed to exclude hematologic disorders. Other therapies need to be further explored and standardized. The efficacy of various therapies for ovulatory type of eclampsia varies, and individualization should be emphasized.