Primary amenorrhea is defined as the absence of menstruation in women who have reached the age of 16 years despite the development of secondary sexual characteristics, or the absence of menstruation and the absence of secondary sexual characteristics at the age of 14 years. The incidence of primary amenorrhea is much lower than that of secondary amenorrhea, accounting for about 5% of amenorrhea, with abnormal development of the lower genital tract being the most common.
1.Classification
1.1 Classification according to the site of amenorrhea lesion
1.1.1 Lesions of the lower genital tract and uterus: abnormal development of the lower genital tract, congenital absence of the uterus or absence of endometrial function resulting in amenorrhea. Jin Meiyuan, Department of Obstetrics and Gynecology, Zhejiang Tongde Hospital
1.1.2 Ovarian pathology: amenorrhea due to non-functioning or low functioning ovaries.
1.1.3 Anterior pituitary lesion: amenorrhea caused by abnormal secretion of gonadotropin (Gn) due to pituitary lesion.
1.1.4 Central nervous system (hypothalamus) lesions: amenorrhea caused by dysfunction of the central nervous system and hypothalamus affecting the function of the pituitary-ovarian axis, or defective secretion of hypothalamic gonadotropin-releasing hormone (GnRH) caused by congenital diseases or malformations of brain development and tumors. In addition, abnormal thyroid, adrenal and pancreatic functions can also lead to amenorrhea.
1.2 Classification according to the development of secondary sex characteristics
1.2.1 Primary amenorrhea due to the presence of secondary sex characteristics: The ovaries develop and function normally, so there is secondary sex characteristic development. For example, Müllerian duct hypoplasia syndrome, genital atresia, ovarian insensitivity syndrome, true hermaphroditism, etc.
1.2.2 Primary amenorrhea with lack of secondary sex characteristics: most commonly associated with primary hypogonadism and defective ovarian estrogen secretion. For example, Turner syndrome, simple gonadal hypoplasia and rare ovarian and adrenal-specific 17α hydroxylase defects. In addition, olfactory deficiency syndrome and somatic pubertal delay also manifest as secondary sexual characteristics deficiency.
2. Etiology
2.1 Lower genital tract and uterine amenorrhea
2.1.1 Hymenal atresia (imperforatehymen): also known as imperforate hymen, is more common. It is caused by the non-luminalization of the urogenital sinus tissue at the end of the vagina during development and normal development of the Mullerian duct. The blood accumulation in the vagina, uterine cavity and fallopian tubes gradually forms because of the inability of menstrual blood to flow out, which can eventually lead to pelvic blood accumulation.
2.1.2 Congenitalabsenceofvagina: It is caused by the underdevelopment or hypoplasia of the Mullerian ducts, or the obstruction of vaginal cavitation. It is often associated with a hypoplastic uterus or no uterus or only a primordial uterus. Ovarian function is usually normal, often combined with urinary tract and spinal anomalies.
2.1.3 Transverse vaginal septum (trausverseseptaeofvagina): it is mainly caused by unlumenized vaginal plate and can be located anywhere in the vagina. The upper vaginal septum is often incomplete and the lower vaginal septum is often complete. Complete transverse septum has a clinical presentation similar to an imperforate hymen due to obstruction of menstrual blood drainage.
2.1.4 Atresiaofvagina: The Mullerian duct is normally developed, but it is due to the failure of the urogenital sinuses to participate in the formation of the lower vaginal segment, often combined with external genital hypoplasia.
2.1.5 Atresia of the cervix: it is caused by congenital abnormalities and is extremely rare. If the patient has no endometrium, it only presents as primary amenorrhea; if there is endometrium, the clinical presentation is similar to congenital absence of vagina.
2.1.6 Congenitalabsenceofuterus: The mullerian ducts are not developed or stop developing early, resulting in congenital absence of the uterus. It is often combined with absence of vagina, normal ovarian development and presence of secondary sexual characteristics.
2.1.7 Primordial uterus: The two sides of the primordial uterus develop normally in the early stages, but stop developing soon after they meet in the middle stages, leaving only a narrow, fibrous and muscular structure with no cavity, often combined with congenital absence of vagina.
2.1.8 Mullerian agenesissyn-drome syndrome: also known as M-R-K-H syndrome, is caused by mullerian duct development stalled at different times or asynchronous development. It is often associated with developmental defects of other mesodermal organs. It may manifest as congenital absence of vagina, absence of uterus, primordial uterus and various types of uterine malformations, and is often accompanied by abnormal development of the urinary system and skeletal malformations. The ovaries are normally developed.
2.2 Ovarian amenorrhea
2.2.1 Turner’s syndrome: This is due to the deletion or mutation of one X chromosome, karyotype 45, X0. It is characterized by ovarian dysplasia, absence of secondary sexual characteristics, and uterine hypoplasia. The patient has a characteristic physical appearance. Often combined with abnormalities of the urinary and cardiovascular systems [1].
2.2.2 Solitary gonadal hypoplasia: congenital ovarian hypoplasia with a karyotype of 46, XX or 46, XY (i.e. Swyer’s syndrome). Possible causes are early gestational viral infections and metabolic effects that result in destruction of their gonads and prevent further development, or gonadal hypoplasia due to inactivation of genes that determine gonadal development.
2.2.3 Ovarian resistance syndrome (resistovarysyndrome): Ovarian insensitivity syndrome, rare. It may be due to the lack of Gn receptors or Gn receptor mutations in the ovary, or the lack of effective ovarian response to endogenous or exogenous Gn due to abnormal ovarian local regulators. The patient presented with primary amenorrhea and normal growth and development. The karyotype is 46,XX.
2.2.4 Androgen insensitivity syndrome (androgeninsensitivitysyn-drome): it is a male pseudohermaphroditism. The chromosome is 46, XY, and the gonads are testes, which secrete testosterone but do not exert biological effects due to defective testosterone receptors in target tissues, so testosterone is phenotypically female through aromatization to estrogen.
2.2.5 Ovarian enzyme deficiency: such as 17α hydroxylase deficiency syndrome and 17 and 20 carbon chain cleavage enzyme deficiency syndrome. 17α hydroxylase and 17 and 20 carbon chain cleavage enzymes play a critical role in the androgen synthesis pathway, if congenitally deficient, ovarian estrogen and androgen synthesis is blocked and follicle development is impaired, leading to primary amenorrhea. It is often associated with hypertension, hyperkalemia and hyperprogesteronemia, and no secondary sex characteristics develop.
2.3 Pituitary amenorrhea
2.3.1 Pituitary monogenic Gn deficiency: The pituitary gland is normal except for Gn deficiency in secretion, which may be due to abnormalities in Gn subunits or receptors. Blood follicle stimulating hormone (FSH), luteinizing hormone (LH) and estrogen levels are low. The main manifestations are primary amenorrhea, non-development of gonads, sexual organs and secondary sexual characteristics.
2.3.2 Pituitary growth hormone deficiency: caused by insufficient secretion of anterior pituitary growth hormone (GH). Patients have a child-like body shape and appearance, short stature, but well-proportioned and normal intelligence. After puberty, both internal and external genitalia and secondary sexual characteristics do not develop, manifesting as primary amenorrhea.
2.3.3 Prolactinoma: It is a common functional adenoma of the anterior pituitary gland that secretes prolactin (PRL) and has a slow growth rate. Clinical symptoms are amenorrhea and lactation.
2.3.4 Growth hormone tumor: It is an anterior pituitary eosinophilic tumor that can secrete large amounts of growth hormone (GH). If it develops before adulthood, it often presents as gigantism with gonadal hypoplasia and primary amenorrhea.
2.3.5 Empty-sellasyndrome: If the patient has abnormalities in the butterfly saddle that are not caused by a tumor, the patient has empty-sellasyndrome. It is a congenital defect of the saddle septum that causes the subarachnoid space to fall into the pituitary fossa, resulting in extrusion of the adenohypophysis and separation from the hypothalamus, manifesting as amenorrhea and lactation. It can also occur secondary to surgery, radiation therapy or pituitary tumor infarction.
2.4 Hypothalamic amenorrhea: It is a common cause of low Gn secretory amenorrhea and generally requires exclusion of pituitary lesions to establish the diagnosis. It is often due to abnormal secretion of GnRH pulses in the hypothalamus as a result of organic or functional disorders of the central nervous system. Clinical features are: low or normal Gn, normal PRL, and normal pterygoid saddle.
2.4.1 Anorexia nervosa: It is a very serious and even fatal eating behavior disorder. The etiology is unclear and is currently thought to be due to biological, social, and psychiatric factors.
2.4.2 Athletic amenorrhea: common in competitive and long-distance runners and dancers, mostly secondary to amenorrhea.
2.4.3 Kallmarm syndrome: a disorder of hypogonadism and hypogonadism caused by lack of GnRH secretion and accompanied by loss or hyposmia of the sense of smell. It manifests as primary amenorrhea, non-developmental or poorly developed secondary sexual characteristics, low Gn levels, and very low E2 levels. Normal female karyotype, loss of smell or hyposmia since childhood, especially inability to distinguish between scent and coffee.
2.4.4 Craniopharyngioma The preferred site is the anterior part of the funnel of the pituitary stalk above the pterygoid saddle, which is a common hypothalamic tumor. The tumor often causes intracranial hypertension, visual impairment, and abnormal hypothalamic and pituitary functions due to compression of the pituitary stalk. The onset of the disease manifests as primary amenorrhea, sexual infantilization, and growth disturbance before puberty, and may cause obesity reproductive incompetence syndrome.
2.4.5 Laurence-Moon-Biedl syndrome: also known as Biedl-Bardet syndrome, is an autosomal recessive genetic disorder. Clinical manifestations are obesity, gonadal hypoplasia, retinitis pigmentosa, and mostly associated with polydactyly. It is more common in the offspring of consanguineous marriages.
2.5 Other
2.5.1 Hypothyroidism: Those with onset at an early age are called cretinism and have typical phallic features. Serum T3 and T4 are low, and thyroid stimulating hormone (TSH) is significantly elevated. The clinical presentation is mostly primary amenorrhea. Hyperthyroidism rarely leads to primary amenorrhea.
2.5.2 Congenital adrenocortical hyperplasia: The common cause is a deficiency of one or more hormone synthesis enzymes, resulting in impaired synthesis of adrenocortical and ovarian hormones. The most common is 2l hydroxylase deficiency.
2.5.3 Type 1 diabetes mellitus: i.e. insulin-dependent diabetes mellitus. The incidence of primary amenorrhea is 4-6 times higher than that of non-diabetic patients, and in those with onset before the age of 10, menarche is delayed by 1 to 3 years compared to normal girls. type 2 diabetes rarely causes primary amenorrhea.
3. Treatment
3.1 Lower genital tract and uterine amenorrhea: First, a gynecological examination should be performed to confirm the presence of mullerian duct stage abnormalities, such as nonporous hymen, absence of vagina, transverse vaginal septum and cervical or uterine agenesis. Except for rare uterine anomalies (uterus without cavity; cavity without endometrium), this type of occlusion is often seen for abdominal pain due to accumulation of blood in the vagina, uterus and abdomen. Patency of the genital tract should be reestablished by early incision and drainage at the lowest point of the Mullerian duct obstruction. Delayed treatment of distal obstruction of the female genital tract can lead to endometriosis and pelvic inflammatory disease, eventually leading to infertility, so surgery should be performed as soon as possible after diagnosis. Among all surgeries, vaginoplasty is more complicated and difficult. Currently, the commonly used methods include peritoneal, sigmoid, thigh flap, vulvar flap and amniotic membrane vaginal substitute. In recent years, the use of progressive dilatation (parietal compression) instead of vaginoplasty has been advocated as the first-line treatment option because of its non-invasive and high success rate, provided that the vaginal depression is deep enough (2-4 cm). In the absence of a uterus or a primordial uterus, there is no effective treatment and uterine transplantation is only theoretically possible. In case of atresia of the primordial uterus or cervical canal with periodic abdominal pain or accumulation of blood in the uterine cavity, the uterus should be removed.
3.2 Ovarian amenorrhea: the pathogenesis is unknown, so the main treatment is symptomatic. patients with Turner syndrome are given growth promotion therapy, growth hormone can be used as early as 5-6 years of age, and hormone supplementation therapy (HRT) should be used. Gonads with Y chromosomes should be surgically removed to prevent tumors and androgenesis. For example, in patients with XY simple gonadal hypoplasia, the hypoplastic or abnormally located testes are most likely to develop tumors and should be surgically removed, while patients with XX simple gonadal hypoplasia are generally less likely to develop tumors and do not require surgery. Patients with various congenital ovarian hypoplasia and 17α hydroxylase deficiency should use HRT for a long time to promote the development of female secondary sexual characteristics, induce artificial menstruation, prevent osteoporosis and protect the cardiovascular system, and obtain pregnancy by in vitro fertilization embryo transfer with donor eggs.
3.3 Pituitary amenorrhea
3.3.1 Monogenic Gn deficiency: HRT is used for those without fertility requirements, and exogenous Gn ovulation treatment is available for those with fertility requirements.
3.3.2 Growth hormone deficiency: apply growth hormone, the earlier the treatment is started, the better the effect.
3.3.3 Prolactinoma: Pharmacological treatment: Bromocriptine is preferred, the initial amount is 1.25mg per day orally, if there is no discomfort, the dosage can be increased gradually, the usual amount is 5.0~7.5mg per day, if the oral reaction is severe, vaginal dosage can be used, the usual amount is 2.5~5.0mg per day. Surgery is indicated for those who have obvious pressure symptoms and failed to take medication; those who cannot tolerate or fail to take medication; invasive pituitary adenoma with cerebrospinal fluid nasal leakage; non-functional tumors; recurrent pituitary tumors. Generally, trans-sinus approach is used. Radiation therapy is used for patients who are ineffective in drug and surgical treatment or cannot tolerate the side effects of drugs; invasive tumors; postoperative residual or recurrent tumors; and those who are contraindicated to surgery or refuse surgery.
3.3.4 Growth hormone tumors: growth hormone inhibitor analogs (SSTa), are widely used in the treatment of pituitary GH adenomas [4]. Surgery or radiation therapy may also be performed.
3.3.5 Pituitary destruction: HRT is used for those without fertility requirements, and exogenous Gn ovulation treatment is available for those with fertility requirements.
3.4 Hypothalamic amenorrhea
3.4.1 Functional hypothalamic amenorrhea: give mental comfort and guidance; encourage eating gradually in anorexia nervosa; reduce exercise and supplement nutrition in athletic amenorrhea. Estrogen and progesterone sequential artificial cycles are available to stimulate the hypothalamic-pituitary-ovarian axis to restore normal function.
3.4.2 allmann syndrome: Since the gonads still respond to Gn, application of exogenous Gn can induce ovulation, but it is not effective for clomiphene. This patient should be treated with estrogen and progestin supplementation for life. There is no effective treatment for hyposmia.
3.4.3 Craniopharyngioma: Once diagnosed, immediate surgery or radiation therapy should be performed.
3.5 Other endocrine diseases: The main focus is to treat the primary disease.