37. Amenorrhea TSH Prolactin Progestational challenge TSH↑ Withdrawal bleed ＋ Withdrawal bleed － Hypothyroidism Normal prolactin Normal TSH Anovulation Estrogen and progenstin cycle Withdrawal bleed － End organ problem
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40. Differential diagnosis of amenorrhea - + anovulation but follicle development - - Anovulation. No lollicle Disorder of central nervous system - - Anovulation. No follicle Disorder of pitutary - - Anovulation, no follicle Disorder of ovary + + Normal ovulation Disorder of uterine and outflow tract P E FSH LH Ovarian function amenorrhea
41. Treatment of amenorrhea Disorder of central nervous system Disorder of pitutary Disorder of ovary Disorder of uterine and outflow tract amenorrhea anovulation but follicle development Anovulation. No lollicle Anovulation. No follicle Anovulation, no follicle Normal ovulation Ovarian function P - + E+P - - E+P - - E+P - - surgery + + treatment P E FSH LH
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Hinweis der Redaktion
闭经的诊治也令很多妇科临床医生感到困惑。 Lots of gynecologists are confused at the diagnosis and treatment of amenorrhea.
闭经是指月经停止。以往的分类将闭经分为原发性闭经和继发性闭经。但现在的观点，是将闭经的概念定义为以下三点： 1 。。。。。。 2 。。。。。。 3 。。。。。。事实上，前两点就是原发性闭经，第三点是继发性闭经。 Amenorrhea is the absence of menses. Amenorrhea was previously classified as primary amenorrhea and secondary amenorrhea. nowadays,the definition of amenorrhea :1…( 看 ppt) 2….3… as the matter of fact, the first and the second one is primary amenorrhea; the third point is secondary amenorrhea.Amenorrhea is the absence of menses.
正常月经来潮的基本要素：为了便于理解和记忆，我们将 H-P-O-U 轴自下而上分为四个区，第一区是经血流出道，包括产生月经的子宫；第二区是卵巢；第三区是垂体；第四区是下丘和中枢神经系统。 The elements of normal menstruation : in order to understand and memorize, we can divide H-P-O axis into four compartments from bottom to top. The first compartment is the outflow tract including uterus that menses derive from, the second compartment is the ovary, the third compartment is the anterior pituitary, the last compartment is hypothalamic and central nervous system.
四个区的自上而下的正向调节，以及自下而上的正负反馈调节，使得每个月有规律的月经来潮。 Regular menses depend on positive regulation from top to bottom as well as functional feedback mechanism from bottom to top.
当 H-P-O-U 轴的任何一层面（区）出现障碍，就可能引起闭经。 Amenorrhea may be caused by any minimal alteration in the hypothalamic-pituitary-ovarian axis
因此，我们也可以更通俗地将闭经分为子宫性闭经，卵巢性闭经，垂体性闭经，下丘脑性闭经。 Therefore, we can also classify amenorrhea according to H-P-O axis as …….
在诊断闭经前，对于以往月经正常的有性生活史的女性，一定要首先排除妊娠。 As for the women who have regular menses and sexual activity, we have to rule out the pregnancy before making the diagnosis of amenorrhea.
当然，还有其它生理情况引起闭经要考虑，例如：哺乳期，绝经后。性激素的使用期间，特别是避孕药，也可以引起闭经。 Of course, there are some other physiologic situations to be considered, such as, lactation, postmenopause, the use of hormone,especially, contraceptive, which can also lead to amenorrhea.
下面，我们就来认识一下各层面的闭经的常见原因。第一区：子宫性闭经或经血流出道障碍，常见的疾病是： Asherman’s 综合症，苗勒氏管发育不全，雄激素不敏感综合症，子宫内膜结核。 So ,let’s focus on some common reasons of amenorrhea. The first compartment is the disorders of the outflow tract or uterus .Common diseases include ……
本图示 Asherman’s S yndrome 通过宫腔碘油造影见到子宫腔变形狭窄的形状。 This picture demonstrates the configuration of uterine cavity from a patient with asherman’s syndrome undergoing hysterosalpingogram. It becomes distorted and narrow.
引起 Asherman’s S yndrome 的常见原因是产后刮宫或人工流产刮宫损伤了子宫内膜基底层，也可以是宫腔手术引起。可以通过宫腔镜检查或超声造影进行诊断。 Asherman’s S yndrome 常常引起闭经，流产，痛经，月经过少，因此需要治疗。治疗的方法包括：宫腔镜切开粘连，再放置 IUD ，或术后于宫腔内放置小儿双腔导尿管，以 3 ml 液体充盈气囊， 7 天后取出，同时辅助大剂量雌激素治疗，以促进子宫内膜修复。 Asherman’s syndrome usually occurs in patients with risk factors for endometrial or cervical scarring. Such risk factors include a history of postpartum curettage, uterine surgery. Asherman’s syndrome can be found through hysteroscopy and hysterosalpingography. Asherman’s syndrome presents as amenorrhea, abortion, dysmenorrhea, hypomenorrhea. so the proper treatment is important. Adhesions in cervix and uterus (ashermann syndrome)can be removed using hysteroscopic resection with scissors or electrocautery. An intrauterine device or pediatric foly catheter filled with 3ml of fluid should be placed in the uterine cavity for 7days postoperatively. A 2-month course of high-dose estrogen therapy with monthly progesterone withdrawal is used to prevent reformation of adhesion.
苗勒氏管发育异常：胚胎时期，女性生殖道由两条苗勒氏管发育向中线融合形成中空的腔道，如：两条输卵管，一个子宫腔，一条阴道，且阴道通向体外开放。 During the embryo period, Mullerian ducts form laterally to the mesonephric ducts. They grow caudally and then medially to fuse in the midline. At last, they develop into two fallopian tubes, one uterus and one vagina open to outside.
如果在生殖道分化形成过程中出现中线融合障碍，就会导致各种生殖道畸形的发生。如：先天性无阴道，阴道部分闭锁，双子宫，双角子宫，纵膈子宫，单角子宫，残角子宫，阴道横隔，阴道斜隔等，可造成经血潴留。 The disorder of the fuse of Mullerian ducts will lead to genital tract abnormalities involving various types of uterovaginal malformations.such as,double uterus,bicornuate uterus,septate uterus,unicornuate uterus, rudimentary horn of uterus, transverse vaginal septum, et al, which might cause the retention of menstrual bleeding.
处女膜闭锁引起经血潴留，引起阴道扩张，宫腔扩张，输卵管积血。严重者引起盆腔积血和子宫内膜异位症。 Blockage of the outflow tract with an intact endometrium frequently cause cyclic pain without menstrual bleeding in adolescents. The blockage of blood flow in Imperforate hymen patients can cause dilatation of vagina and uterine cavity, and hematosalpinx. Hematometra and endometriosis may develop in severe condition.
苗勒氏管发育不全综合征，原因不明，表现为无阴道，无子宫，无输卵管，但有正常的卵巢，因此，不影响生长发育和第二性征。染色体型为 46 ， XX 。血清性激素水平正常。该患者常常有 15-30% 的机率合并肾和骨骼畸形． The etiology of MRKH syndrome remains uncertain till now. The patients have normal ovaries with normal genotype and serum hormone level, but no vagina, uterus and even fallopian tubes. So, she has normal physical development and secondary sex characteristics. Usually, 15 to 30 percent of these patients present with kidney and bone malformation.
雄激素不敏感综合征：具有男性染色体，但具有女性的外表，乳房发育，女性外生殖器官，无子宫，具有雄性及雌性性腺组织。此病例应在青春期后尽快切除性腺，以防恶变。以后给予雌激素替代治疗。 Phenotypic females with complete congenital androgen insensitivity (previously called testicular feminization) develop secondary sexual characteristics but do not have menses. These patients are male pseudohermaphrodites. Genotypically, they are male but have a defect that prevents normal androgen receptor function, leading to the development of the female phenotype. Testes rather than ovaries are present in the abdomen or in inguinal hernia because of the presence of normally functioning genes on the Y chromosome. the testes should be completely removed after pubertal development in order to prevent malignant degeneration. Bilateral laparoscopic gonadectomy is the preferred procedure for removal of intra-abdominal testes.
苗勒氏管发育不全综合征较雄激素不敏感综合症发病率高．此图，对两种常常引起原发性闭经的子宫层面的疾病特征进行了比较． The incidence of MRKH syndrome is higher than that of androgen insensitivity. This chart illustrates the comparison on characteristics between these two diseases that are chief reason for primary amenorrhea.
我们对第一区闭经的特征进行一个小结：具有正常的染色体核型，子宫缺如或阴道闭锁，具有正常子宫合并阴道膈形成，处女膜闭锁．患者具有正常的血清促性腺激素和性激素水平． Let’s make a summary on the features of compartment 1 amenorrhea: normal genotype, absent uterus or vagina atresia, normal uterus and vaginal septum, imperforate hymens, normal GnRH and sexual hormone level.
第二区：卵巢性闭经。常见有染色体异常，抵抗性卵巢，卵巢早衰。 The second compartment (ovarian amenorrhea) commonly include chromosome anomaly, resistance ovarian syndrome and premature ovarian failure.
其它引起卵巢性闭经的原因还包括放射线或化疗药的损伤卵巢、感染、自身免疫性疾病。 The etiology of ovarian amenorrhea also includes iatrogenic causes (radiation and chemotherapy) ,infection, and autoimmune disorders.
Turner’s Syndrome ：存在一条染色体缺失，常见的染色体核型为 45 ， XO ，当然还有其它是嵌合体，如 45 ， X/46 ， XX 等。此类胎儿往往在早期妊娠时已发生流产。 Turner’s Syndrome is absent of one chromosome. The common genotype is 45,XO, also including other mosaicism such as 45 ， X/46 ， XX and so on. Fetus with this syndrome are often aborted spontaneously during early stage.
Turner Syndrome 具有特殊的外表：身材矮小，颈蹼，肘外翻，盾胸，乳房不发育，乳头间距开，常合并心血管畸形。 Turner syndrome patient has special appearance: short stature, webbing of neck, cubitus valgus, breast agenesis, widely spaced nipples, which are easily seen on physical examination.
Turner Syndrome 的患者常常较同龄人发育滞后，加上有特殊的外表特征，一般容量辨识． Turner Syndrome patients often lag behind their peers in development. Coupled with special appearance characteristic, it is easy to identify these patients.
XY gonadal dysgenesis (Swyer ’ s S) 和 Gonadal agenesis 属不明原因的性腺发育不全，患者具有女性外表，身材发育正常，原发闭经．含Ｙ染色体者成年后也要尽快切除性腺以防恶变． XY gonadal dysgenesis (Swyer ’ s S) and Gonadal agenesis belongs to unidentified gonadal dysgenesis. Patients present as female appearance, normal physical development, primary amenorrhea. In case of malignancy, gonadectomy should be performed as soon as possible on those patients with Y chromosome after puberty.
抵抗性卵巢 : 原因不明，可能是ＧＮ受体缺陷，具有正常的 FSH 和 LH 水平，卵巢大小正常，但卵泡不发育． Ovarian Resistance Syndrome: reasons remain unclear; Gn receptor may be defective; with normal level of FSH and LH; with normal size of ovaries; follicles fail to progress
卵巢早衰是指 40 岁以前卵泡已消耗完毕，可因先天性的因素，如染色体缺失，嵌合体，也可因感染，射线或化疗药物，自身免疫性因素，也有原因不明者，称特发性卵巢早衰． POF is defined as follicular depletion before age 40. It can be caused by congenital factors such as absence of chromosome and mosaicism. It also can be caused by infection, radiation, chemotherapy and autoimmune factors. Idiopathic POF refers to the situation that the etiology remains unclear.
我们对第二区闭经 - 卵巢性闭经和特征进行小结 : 由染色体异常引起性腺不发育（条索状性腺），或不明原因性腺不发育，或性腺对促性腺激素抵抗，或卵巢早衰，均表现为 FSH ， LH 升高，性激素水平低下，有正常的生殖器官。 Let’s make a summary on the features of compartment 2 ovarian amenorrhea: gonadal agenesis (cord-like gonad) caused by chromosome abnormality ,or without clear pathogenic factors, or gonad resistance to gonadotropin, or POF. All of them present as elevated FSH and LH level, low sexual hormone level, and normal reproductive organs.
Prolactin Secreting Adenoma 是常见的垂体前叶肿瘤，但许多垂体微腺瘤生前无症状，死后病理解剖才发现． Prolactin Secreting Adenoma 增大可压迫视交叉引起视野受损，头痛，由于分泌大量的ＰＲＬ抑制了Ｈ－Ｐ－Ｏ轴功能，引起闭经，患者有溢乳表现． Prolactin Secreting Adenoma is a common kind of anterior pituitary tumors. Most of patients are asymptomatic and would not be diagnosed until pathological anatomy after death. The compression of optic chiasma by augmentation of Prolactin Secreting Adenoma will lead to headache and defect of visual field. A large number of PRL secreted inhibit the function of H-P-O axis and cause amenorrhea. Some patients present as galactorrhea.
Sheehan’s syndrome 常常发生于产后出血后，垂体缺血坏死引起，产后早期引起无乳继而因性腺功能低下发生闭经，性毛脱落。严重者除血清 FSH ， LH 水平下降，还可发生肾上腺皮质功能减退及甲状腺功能减退。 Sheehan’s syndrome often take place after postpartum hemorrhage which lead to the pituitary necrosis caused by ischemia. Agalactia occurs in early puerperium and then amenorrhea follows because of gonadal dysfunction. Sex hair sheds. In severe patients, we could find not only the decrease of serum FSH and LH, but also hypoadrenocorticism and hypothyroidism.
第四区闭经：下丘脑性闭经，可以因为心理压力，减肥厌食，运动量过大（如运动员）引起 GNRH 分泌失去正常切律，或药物干扰了中枢神经递质，引起闭经。当然，还有下丘脑的器质性病变，如肿瘤等占位性病变也可引起闭经。 Kallmann syndrome 是一种染色体异常引起的遗传性疾病，表现为闭经、性幼稚，嗅觉丧失。 Compartment 4 amenorrhea: hypothalamic amenorrhea. psychological pressure, diet anorexia, excessive movement (such as athletes) may cause the loss of normal rhythm of GnRH secretion. drugs could also interfere with central nervous system transmitter, then cause amenorrhea. Meanwhile, there are organic lesion of the hypothalamus such as space-occupying lesion like tumors that can also cause amenorrhea. Kallmann syndrome is a kind of hereditary disease caused by chromosome abnormality and presents as amenorrhea, sex infantilism, and anosmia.
我现小结一下第三区和第四区闭经的特征：具有正常的卵巢和子宫，由于各种原因引起垂体或下丘脑功能下降，或器质性病变引起结构受损，导致低促性腺激素性闭经。 Now let’s make a summary on the features of compartment 3 and 4 amenorrhea: normal ovary and uterus; dysfunction of pituitary or hypothalamus caused by various reasons; or configuration damage caused by organic disorder that lead to hypo-gonadotropin amenorrhea.
闭经的诊断，关键在于病因学诊断，因此，询问病史（包括是否有月经史，出生史，生长史，用药史，是否有周期性腹痛等）能获得较多信息，通过详细的体格检查和妇科检查发现体格发育的性情，生殖器官发育状况。实验室检查在闭经的分类诊断中具有重要意义。以下我们以几张闭经诊断过程中常用的实验室流程图来总结闭经的诊断规范。 The key to the diagnosis of amenorrhea lies in the diagnosis of etiology. So, more information could be obtained through a detailed history collection including menstrual history, birth history, growth history, medication history and whether there is a cyclical abdominal pain or not, etc. detailed physical examination and gynecological examination revealed the development of physical and genital development. Laboratory examination is of great importance in the classification diagnosis of amenorrhea. Then we come to summarize the norm of amenorrhea diagnosis through some laboratory flowcharts commonly used in the process of amenorrhea diagnosis.
第一：闭经患者首先进行血清 TSH ， PRL 检测，进行黄体酮试验。如果 TSH 升高，可能提示甲状腺功能低下，应做进一步检查。黄体酮试验阳性（停药后有撤退性出血），而 PRL 、 TSH 正常，说明无排卵引起的闭经。 Firstly, serum TSH and PRL test, and progestational challenge were performed. If TSH is elevated ,it might suggest hypothyroidism, then further examination should be done. Withdrawal bleeding after progestational challenge, along with normal PRL and TSH level, demonstrate amenorrhea caused by anovulation.
接下来我们要检查患者的血 FSH ， LH 水平，如果下降或正常，属垂体或下丘脑性闭经，应进行颅脑 MRI 检查以排除器质性疾病。如果 FSH 和 LH 升高，应考虑是卵巢功能衰退引起的闭经。 Then we examine the serum FSH and LH level. If they are in a low or normal situation, it might suggest pituitary or hypothalamic amenorrhea, and brain MRI examination should be carried out to exclude organic diseases. If FSH and LH increase, amenorrhea should be considered to be caused by recession of ovarian function.
如果黄体酮试验阴性（停药后无撤退性出血），应使用雌激素和孕激素序贯用药，如停药后仍无撤退性出血，应属于子宫性闭经。 If withdrawal bleeding did not take place after progestational challenge, estrogen and progestin cycle should be prescribed. If there is still no withdrawal bleeding, diagnosis of uterine amenorrhea is quite certain.
最后，我推荐大家有空可以阅读一本妇科内分泌的经典专著： Clincal Gynecologic Endocrinology and Infertility At last, I recommend a classic gynecological endocrine monographs (Clincal Gynecologic Endocrinology and Infertility) for you to read at spare time.
