I. Abnormal puberty development
(A) Female homosexual precocious puberty
[Definition]: The development of female sexual characteristics in girls before the age of 8, or the first menstruation before the age of 10.
[Etiology and classification]: There are two categories.
1, true or dependent on GnRH precocious puberty: due to premature activation of the hypothalamic-pituitary-ovarian axis of the central nervous system (CNS). The process is the same as normal pubertal development. Causes of premature activation are: Yang Guoqing, Department of Endocrinology, Beijing 301 Hospital
(1) Idiopathic or somatic precocious puberty: its cause is not elucidated.
(2) Cerebral precocious puberty: it is less common. For example, posterior hypothalamic gray nodal malformation tumor, craniopharyngioma, etc. Other
CNS abnormalities such as radiotherapy or trauma, inflammation, hydrocephalus, subarachnoid cysts, etc. It has been reported that 60% of true precocious puberty is idiopathic, 16% is hypothalamic malformation tumor, and the rest is other CNS abnormalities.
(3) Congenital adrenocortical hyperplasia: If treated after the age of 4-8 years, the release of androgenic central
After feedback inhibition, it can cause increased secretion of GnRH and Gn and true precocious puberty.
(4) Primary hypothyroidism: caused by the cross-talk of excessive TSH on FSH receptors.
Such patients have hyperprolactinemia and lactation without growth acceleration.
2) Pseudo- or non-GnRH-dependent precocious puberty: caused by premature secretion of estrogen from peripheral sources. The causes are.
(1) Ovarian multiple follicular cysts: the most common. On autopsy and ultrasonography in normal girls aged 4-8 years, multiple ovarian microcysts, <9 mm in diameter, which appear and disappear, and are often non-functional, may be a normal ovarian response to prepubertal pulsatile GnRH secretion. Sometimes these nonfunctional ovarian follicles may transform into autonomous estrogen-secreting follicular cysts, causing pseudoprecocious puberty. The mechanism is unclear.
(2) Ovarian estrogen-secreting tumors (granulosa cell tumors, gonadotroph tumors, etc.) and adrenal estrogen-secreting tumors.
(3) Exposure to exogenous estrogens.
(4) McCune-Albright syndrome: consists of a triad of autonomic hyperfunction of one or more endocrine glands
The syndrome consists of a triad of autonomic hyperfunction of one or more endocrine glands (most commonly ovarian autonomic flavinized follicular cysts causing pseudoprecocious puberty), multiple heterogeneous proliferation of bone fibers, and irregularly margined cutaneous café au lait spots. The cause is a mutation in the cell membrane receptor-coupled agonistic guanine nucleotide-binding protein alpha gene.
3.Premature breast development: It is a variation of normal pubertal development, and it is also classified as “pseudoprecocious puberty”. It may be
It may be related to the irregular fluctuation of pituitary FSH level or target organ hypersensitivity. It is a self-limiting disease. It has been reported that after 3-5 years of follow-up, 57% of children with this disorder have no change in their condition, 32% have regression of breast development, and 11% have progression of breast development, but no other symptoms of puberty. However, 14% of them have been reported to have early stages of true precocious puberty.
[Clinical presentation]
Children with true precocious puberty show hyperestrogenemia, breast development, enlarged labia minora, and hyperpigmentation; changes in vaginal mucosa maturation, rightward shift of cytologic smear (V slice) maturation index (MI), and early onset of menstruation. Pubic hair often does not appear earlier. Bilateral ovarian and uterine enlargement with multiple large follicular cysts in the ovaries can be seen on anal examination and ultrasound. Ovulation and fertility may be present. However, psychosexual maturation is not advanced. The child’s height growth is accelerated prematurely and the bone scale closes early due to advanced bone age, so the final height may be shorter. The progression of the disease can be fast or slow. Cerebral precocious puberty may also have neurological symptoms.
Pseudoprecocious puberty also presents with hyperestrogenemia as described above, and may also present with accelerated growth and premature bone age. However, there is no ovulation or fertility. Ovarian masses may be detected on anal examination and ultrasound. In exogenous precocious puberty, a history of exposure to estrogen-containing substances may be traced, and bilateral areola discoloration may be evident; in patients with McCune-Albright syndrome, cutaneous café au lait spots and localized skeletal bulges or deformities may be observed, and irregular hypodense areas may be seen on X-ray.
Premature breast development may be unilateral or bilateral, without vaginal bleeding. The elevation of estrogen is transient and clinically undetectable, and the course of the disease is not progressive and does not affect growth.
[Etiological diagnosis].
It should first be differentiated from premature breast development and other causes of vaginal bleeding (inflammation or trauma, vaginal foreign bodies, vaginal cervical tumors). After the identification of homosexual precocious puberty, it should be identified whether the etiology is located centrally or peripherally?
Detailed questions should be asked about the time of symptom onset, the presence or absence of causative factors, progression; history of previous head trauma, convulsions. V film, bone age, pelvic ultrasonography may be helpful. Blood FSH, LH, E2 basal levels are of limited value. GnRH excitation test LH, FSH response can help to identify the etiology. lH dominant response can confirm ovarian axis activation. fsh dominant is not sure ovarian axis is not activated and should be followed for progression. pseudoprematurity GnRH excitation test response is low.
[Treatment].
True precocious puberty: cranial magnetic imaging (MRI) should be performed and neurosurgical management should be requested if there is an occupying lesion; if there is no evidence of an occupying lesion or other intracerebral disease, idiopathic precocious puberty should be diagnosed.
Idiopathic precocious puberty has been treated with synthetic progestins in the past, which can achieve the purpose of inhibiting the development of sexual characteristics and menstrual flow. The commonly used preparations include vinblodigestrel 2mg/d and levonorgestrel 2-4mg/d. However, they cannot inhibit early skeletal development and do not improve height; long-term use may affect the liver, and some synthetic progestins may also have androgenic activity, so the minimum effective dose is applied. long-acting GnRH agonists became a better treatment option after the 1980s. The available preparations are: leuprolide (suppressant), treprostin (Dapigal or Daphylline), etc., injected once every 4 weeks, 3.75 mg each time; the dose can be reduced by half for those aged less than 6 years. There is a brief period of pituitary excitation at the beginning of the drug, which turns to suppression after about 2-4 weeks. The drug can be discontinued at about 11 years of age, and the first menstruation occurs after about 1 year, after which ovulation and fertility functions are normal. Irregular use of the drug can have the opposite effect; therefore, symptoms, blood E2 levels, height, bone age, repeat pelvic ultrasound and GnRH excitation test should be monitored if necessary. A rare adverse reaction is allergic reaction.
Pseudoprecocious puberty: use targeted treatment according to the etiology, such as removal of the tumor and cutting off exogenous estrogen exposure. Primary ovarian multifollicular cysts can be treated with synthetic progestins or, in rare cases, laparoscopic removal of the cysts, while McCune-Albright syndrome requires treatment with aromatase inhibitors or synthetic progestins. There is no effective treatment for skeletal lesions. Premature breast development requires only observation and follow-up. Care should be taken to exclude the possibility of true precocious puberty.
Psychological treatment: Patiently explain to the child and parents to relieve their worries or anxiety and actively cooperate with the treatment; and protect the child from sexual harassment.
(II) Delayed puberty and sexual infantilism
[Definition]: It refers to girls who have not developed breasts after the age of 13 or have no first menstruation at the age of 15. Sexual infantilism refers to permanent non-development of sex characteristics and sexual organs.
[Etiology and classification] According to its etiology, it can be divided into the following three categories.
1. Somatic or idiopathic delayed pubertal development: due to delayed activation of hypothalamic GnRH pulse secretion and ovarian axis function. Shorter height and delayed bone age, but consistent with height and growth rate. prepubertal response after GnRH stimulation. Once the skeletal age reaches 12-13 years, normal pubertal development occurs naturally, reaching sexual maturity and normal adult height. The parents or sisters of the affected child may also have delayed puberty.
2. Hypogonadotropic hypogonadism is due to insufficient relative or absolute GnRH pulse secretion; or abnormal amplitude and frequency of GnRH secretion.
(1) CNS diseases: tumors such as craniopharyngioma, pineal tumor, ectopic pineal tumor, prolactinoma, etc. Often associated with deficiency of one or more pituitary prohormones, headache, visual field defects, growth disturbance, delayed bone age; CT or MRI can detect occupying lesions. Surgical resection can be performed via transsphenoidal or craniotomy with postoperative radiotherapy. Other CNS disorders such as infection, injury, congenital malformation or after head radiotherapy.
(2) Isolated gonadotropin deficiency: Patients are not associated with other pituitary hormone abnormalities. Kallmann’s syndrome is more common. It is often associated with olfactory disturbances and other malformations. The disease is a non-homogeneous genetic disorder with mutations in the KAL1 gene. It can be autosomal dominant, recessive or X-linked.
(3) Idiopathic pituitary GH deficiency: 2/3 of the patients are caused by hypothalamic GHRH deficiency. MRI reveals pituitary atrophy or pituitary stalk dissection. This is manifested by growth disturbance and delayed puberty.
(4) Functional gonadotropin deficiency: Severe systemic and chronic wasting diseases and malnutrition may lead to delayed puberty. Hypothyroidism and Cushing’s disease are also often associated with delayed puberty.
Anorexia nervosa: It is common in girls who are obsessed with losing weight or who are stressed. Patients are anorexic or have an overactive appetite. There is severe low body weight, hypothermia, hypotension, chilliness, over-exercise, and emotional stress. Have an introverted personality and compulsive behavior. There is delayed puberty, primary or secondary amenorrhea. Pathophysiology: including neuroendocrine metabolic abnormalities, psychosomatic abnormalities and malnutrition. The ovarian axis is hypofunctional. Increased adrenal axis activity, excessive secretion of cortisone, and changes in the thyroid axis are associated with low T3 syndrome. Decreased blood IGF-1 levels, growth hormone may be elevated.
High-intensity athletes or ballerinas, for example, have later pubertal development and first menstruation than girls of the same age due to high exercise and too little body fat. Other factors such as prepubertal hyperprolactinemia and adolescent drug use may also cause delayed puberty.
3. Hypogonadotropic hypogonadism
(1) Turner’s syndrome has abnormalities in the number or structure of the X chromosome. The incidence is approximately 1 in 2000-2500 live births of female infants. The ovaries are striated, lacking follicles and estrogen production, and sexually infantile. There are often physical deformities such as short stature, webbed neck, multifaceted nevus, barrel-shaped chest, and elbow ectropion.
(2) 46,XX and 46,XY simple gonadal hypoplasia: The patient has a female appearance and internal and external genitalia, and her sexual characteristics are not developed and she has primary amenorrhea. 46,XX gonadal hypogonadism is autosomal recessive. 46,XY gonadal hypogonadism is X-sex-linked or, in some cases, autosomal recessive. The presence of Y increases the risk of tumors in the underdeveloped gonads.
(3) Premature ovarian failure before puberty, removal of ovaries at an early age, or damage by radiotherapy or chemotherapy to the ovarian area.
[Diagnosis of delayed puberty and sexual infantilism]
If a girl has passed the age of 13 without sexual development, or if there is no menstrual flow 5 years after the onset of sexual characteristics, FSH, LH and E2 should be measured. If FSH and LH levels are elevated, the cause of the disease is in the gonads. Karyotyping is necessary at this time.
The differential diagnosis of hypogonadotropic hypogonadism and somatic delayed puberty is sometimes difficult. A detailed history, height and weight measurements, and differentiation of the stage of development of the sex characteristics, with attention to the exclusion of cardiac, pulmonary, renal, and gastrointestinal disorders, are necessary. LH, FSH, GnRH excitation test, bone age, CT or MRI of the head, pelvic ultrasound should be checked. If you can’t identify them, it is necessary to follow up and observe them for a period of time.
[Treatment of delayed puberty and sexual infantilism]
In principle, physical delay in puberty should be observed and followed up, and normal puberty will start when the bone age reaches 13 years old.
Sexual infantilism should be treated according to the following principles.
1. Removal and correction of the cause of CNS tumors or disorders can be treated surgically or non-surgically as appropriate. Functional hypogonadotropic hypogonadism can be corrected and adjusted. For example, to improve the nutritional status, we should encourage them to eat and increase their weight; for hypothyroidism, we should correct hypothyroidism; treat endocrine abnormalities such as Cushing’s syndrome and hyperprolactinemia; and strictly prohibit adolescents from taking drugs.
2.Treatment of hypogonadism
(1) Treatment of hypogonadotropic hypogonadism includes the following.
Estrogen and progesterone replacement: to promote the development of secondary sexual characteristics and induce artificial menstruation.
Fertility promotion: GnRH pulse therapy, human postmenopausal gonadotropins, bromocriptine
2) Hypogonadism with hypergonadotropic hypogonadism can only be treated with estrogen and progestin replacement. turner’s syndrome should be started after 13 years of bone age. In gonadal hypogonadism with the presence of Y chromosome, gonadectomy should be performed as early as possible.
3. Growth hormone (GH) therapy: For hypogonadism with short stature or patients with clear GH deficiency, GH therapy should be applied as early as possible. Do not apply estrogen at the same time during GH treatment.
II. Anovulatory dysfunctional uterine bleeding
[Definition]: It refers to abnormal uterine bleeding caused by non-systemic and organic diseases of the reproductive system. Those with puberty onset are anovulatory type, accounting for 70-80% of gonorrhea.
[Etiology and pathophysiology]:The hypothalamic-pituitary positive feedback response to estrogen is not yet established. The incidence of anovulatory menstruation 1-5 years after menarche is 50%-20%. If stimulated by overexertion, stress, or genetic factors such as obesity or insulin resistance at this time, it may cause gonorrhea or polycystic ovary syndrome (PCOS). Patients have irregular follicular development in the ovaries, irregular fluctuations in blood estrogen levels; no induction of blood LH peaks; no luteal formation, low progesterone levels, which cause continuous proliferation or even hyperplasia of the endometrium, irregular shedding, and estrogen withdrawal or breakthrough bleeding, which causes increased or continuous, unpredictable bleeding.
[The type of bleeding is determined by the serum estrogen level and the speed of its decrease, the amount of bleeding may be small or large, the duration and interval may be long or short, and the course of the disease may be long. There may be anemia, hirsutism, obesity, and lactation. It is not usually accompanied by dysmenorrhea. The pelvic examination is normal, and the BBT is monophasic. Serum E2 concentration is equivalent to mid and late follicular levels without cyclic changes. p concentration <3ng/ml. single LH and FSH levels are normal or LH/FSH ratio is too high and cyclic peaks disappear. Endometrial biopsy pathology may show proliferation, simple hyperplasia, compound hyperplasia, endometrial polyp or atypical hyperplasia without secretory phase manifestations. Occasionally, it may be complicated by endometrial adenocarcinoma.
[Diagnosis and differential diagnosis]
1. Ask for detailed menstrual history to make sure that the patient has abnormal uterine bleeding and it must last for a considerable period of time. The evolution of menstrual symptoms and the course of the disease should be understood during the questioning. Related symptoms: secondary sex characteristics, growth, lactation, weight, hair changes, sex life, etc. The examination performed and its results, the treatment received and its effect, especially the medication used in the last 1-2 months.
2. Excluding organic diseases: including excluding non-genital tract (urinary tract, rectum and anus) and other parts of the genital tract (cervix, vagina) bleeding, excluding systemic diseases, mainly blood diseases: thrombocytopenic purpura, aplastic anemia, leukemia, etc. Excluding organic diseases of the external reproductive system: (1) complications of pregnancy (2) tumors: uterine fibroids (submucosal), estrogen-secreting sex cord mesenchymal tumors of the ovary. (3) Endometritis. (4) Genital tract trauma, foreign body. Bleeding of other than medical origin:Improper administration of sex hormones. Whole body physical examination and pelvic examination, whole blood phase examination, coagulation function, blood hCG determination, thyroid function, ultrasonography, diagnostic scraping or endometrial biopsy pathology if necessary.
3. Determine anovulation and etiology: Blood progesterone, LH, FSH, PRL, E2, T determination according to BBT, optional.
[Treatment]:
1.Stop bleeding
(1) Progesterone endometrial shedding method is commonly used for intramuscular progesterone 20mg/d for 3-5 days; or progesterone enanthate (MPA) 6-10mg/d for 10 days. It should only be used for patients with hemoglobin >70g/L. To reduce the amount of withdrawal bleeding, testosterone propionate 25mg/d can be dispensed. in case of high amount of withdrawal bleeding, bed rest should be given, general hemostatic agents, blood transfusion if necessary, without sex hormones.
(2). The estrogen endothelial growth method is only indicated in unmarried adolescent patients and when hemoglobin is <70 g/L. Generally, estradiol benzoate (E2B) is injected intramuscularly, which can be started from 3-4 mg/d in 2-3 injections. If the bleeding does not decrease, gradually increase to 8-12 mg/d. It can also be started at high doses to stop bleeding faster. At the same time, actively correct anemia. After 2 to 3 days of hemostasis, E2B can be gradually reduced to a rate that no longer causes bleeding, until 1mg/d, that is, no longer need to reduce, maintain until about 20 days of medication, or hemoglobin has been higher than 80g/L, then change to progesterone and testosterone propionate endothelial shedding, to end this hemostatic cycle. This method should not be used frequently. The emphasis is on preventing another serious bleeding.
(3). General hemostatic treatment has an adjunctive role. Commonly used are: vitamin K4 or vitamin K3, haemostasis (haemodin), tranexamic acid (torsemide), vitamin C, anisole, and lithopodium.
(4) Diagnostic scraping is generally not used for unmarried patients.
2. Induction of ovulation or control of menstrual cycle
After the bleeding stops, follow up with BBT measurement and check the concentration of serum reproductive hormones at random. Progesterone can be used periodically to make the endometrium shed regularly on schedule. For those with low estrogen levels, sequential estrogen and progestin replacement therapy should be used. Chlordiazepoxide should not be used. The type of uterine bleeding due to hematologic disease should be defined, and long-term endometrial atrophy treatment or surgical removal of the uterus or endometrium should be used according to different prognoses. In case of simple or compound hyperplasia of the endometrium, the cycle can still be controlled with progesterone in the second half of the cycle. However, in case of atypical hyperplasia, the treatment plan should be decided according to the degree of the lesion (mild, moderate or severe) and the age of the patient.
[Prognosis]: The eventual establishment of a normal menstrual cycle in anovulatory adolescent patients is related to the duration of the disease. Normal cycles are established within 4 years of onset in 63.2% of cases, and PCOS may be combined in those with a disease duration longer than 4 years.
C. Polycystic ovary syndrome (PCOS)
[Definition]: It refers to the onset of adolescence and excessive androgen production due to benign proliferation of ovarian follicular cells, resulting in menstrual disorders, persistent ovulation disorders, hyperandrogenism, and ovarian polycystic-like changes. Polycystic ovaries (PCO) and PCOS are two different concepts; PCO is only a morphological sign and can be caused by any disease that causes excessive androgen production in the body and increased production of extraglandular estrone.
[Clinical manifestations]
(a) Symptoms and signs
Irregular menstruation persists after the first menstrual period. The most common cases are sporadic menstruation, secondary amenorrhea and dysfunctional uterine bleeding.
Secondary amenorrhea and dysfunctional uterine bleeding are the second most common, while primary amenorrhea and regular anovulatory menstruation are occasionally seen. The vast majority of patients are anovulatory, while a few may have sporadic ovulation or luteal insufficiency.
Symptoms of hyperandrogenism include hirsutism (about 70% of cases), acne, and occasionally a slightly enlarged clitoris or slightly protruding laryngeal nodes.
Obesity: the incidence is about 50%. If the ratio of waist circumference to hip circumference (WHR) is used as an indicator, WHR > 0.85 is considered as upper abdominal obesity or male obesity.
Acanthosis nigricans: The skin folds of the back of the neck, axillae, and vulva become gray-brown, velvety, flaky, hyperkeratotic lesions with deepened pigmentation. It is a skin change of severe IR.
(II), blood hormone changes
Hyperandrogenemia: serum T, DHT, androstenedione (A2), dehydroepiandrosterone (DHEA) and its sulfate (DS) levels can be elevated, and SHBG decreases so that FT increases more.
Hyperestrogen (E1)emia: The amount of blood E2 is equivalent to normal early and mid follicular phase levels. Hyperandrogenism is converted to E1 in peripheral adipose tissue, with increased blood E1 levels and E1/E2 concentration ratio >1.
The ratio of blood LH to FSH is abnormal: Patients with PCOS have significantly higher follicular LH than normal women and lower FSH, resulting in an increased LH/FSH ratio of 2 to 3 or more. However, it may not be higher in obese patients.
Hyperinsulinemia: PCOS patients have hyperinsulinemia compared to age- and weight-matched controls. Hyperinsulinemia is found in about 30% of lean PCOS patients and in about 75% of obese PCOS patients. After the glucose tolerance test (OGTT), the blood insulin response is hyperactive and the glucose response is normal. When pancreatic β-cell function is depleted, hypoglycemic tolerance or diabetes mellitus develops.
Hyper-PRLemia about 10% to 30% of PCOS patients have mild hyper-PRLemia
(iii) Ultrasound examination of PCO signs
The sensitivity is 92% and the specificity is 97%, when identifying PCO from normal ovaries based on ovarian volume and follicle diameter.
(iv) Clinical typing
In 1999, Yen proposed that non-obese PCOS is true PCOS, with hypersecretion of GnRH-LH and GH-IGF1 system as the main pathophysiological changes; while the pathophysiological changes of GnRH-LH system in obese PCOS patients are modified by obesity, together with the effect of high insulin, which constitutes a variant type of PCOS. In addition, Kahn (1976) found that insulin resistance coexists with acanthosis nigricans, called “hyperandrogenic insulin-resistant acanthosis nigricans syndrome (HAIR-AN syndrome). It is common in young women with very severe IR with hyperinsulinemia, varying degrees of hyperandrogenemia, ovarian PCO or ovarian mesenchymal cell proliferation, and acanthosis nigricans changes.
(E) Recent and long-term comorbidities
Pregnancy comorbidities: increased rate of spontaneous abortion and gestational diabetes mellitus in PCOS compared to non-PCOS patients.
Metabolic syndrome includes: hyperglycemia or hypoglycemic tolerance (IGT), increased TG, decreased HDL-C, hypertension, central obesity, and metabolic syndrome when three of the above five items are present. The core is IR, a common high-risk factor for cardiovascular disease, hypertension and diabetes.
The prevalence of IGT or non-insulin-dependent diabetes mellitus (NIDDM) is increased. There is an increased risk of endometrial hyperplasia and cancer.
[Pathophysiology]
(i) Reproductive axis disorders
Abnormal GnRH/LH pulse secretion leads to uncoordinated Gn secretion: women with PCOS have increased GnRH/LH pulse frequency regardless of obesity.
The frequency of GnRH/LH pulses is increased in women with PCOS regardless of obesity. The amplitude of GnRH/LH pulse secretion is also increased in non-obese PCOS women, resulting in a 3-fold increase in the average 24-hour LH level and an LH/FSH ratio >2-3. Obesity negatively affects the increase in the amplitude of GnRH-LH pulse secretion, resulting in little or no increase in LH levels and a low LH/FSH ratio. Inherent defects, or lack of progesterone effect of sustained estrogen.
Hyperfunction of the LH-vesicular cell system: PCOS patients have excess androgens from the ovaries. It is associated with hyperfunction of cytochrome P450C17α enzyme. The excess androgens are converted to excess estrone in the periphery, which in turn stimulates increased pituitary sensitivity to GnRH and more LH secretion, creating a vicious circle. the absence of cyclic changes in E1 extra-adenous production creates abnormal feedback signals to the hypothalamus pituitary, leading to anovulation and absence of progesterone counteraction.
Impaired function of the FSH-granulosa cell system: dominant follicle selection is impaired in PCOS. Follicular granulosa cells are low in number and lack aromatase activity. However, in vitro, these granulosa cells respond normally to FSH, and it is possible that the local presence of FSH and IGF inhibitors in PCOS follicles blocks aromatase activation. Studies have demonstrated that IGFBP-2 is high and IGF-II is low in PCOS follicular fluid, and IGFBP is the substance that blocks the action of FSH. It may be related to Kaohsiung and high pancreas.
(ii) Metabolic disorders
Selective insulin resistance (IR) refers to the reduced sensitivity of peripheral tissues to the regulatory effect of insulin (INS) glucose metabolism, causing compensatory hyperinsulinemia. However, the sensitivity to the pro-dividing effect of INS is normal. The mechanism of occurrence is unclear and may be secondary to abnormalities in several parts of the insulin action pathway, such as reduced tyrosine kinase activity, GLUT4 transport efficiency and ability to inhibit lipolysis, and excessive serine phosphorylation, causing dysfunction of the signaling system.
Hyperinsulinemia directly stimulates excessive T production in PCOS ovarian mesenchymal cells. insulin synergizes with IGF-I to amplify LH-induced androgen production in vesicular membrane cells. Insulin promotes division and directly causes multiple follicles and ovarian enlargement. High insulin inhibits hepatic SHBG and IGFBP-1 synthesis and increases FT and free IGF-1 levels. Hyperinsulin also promotes cytochrome P450c17α enzyme activity in PCOS. It may promote increased amplitude of pituitary LH pulse secretion.
Ovaries remain sensitive to the role of insulin in regulating sex hormone production, and it is possible that insulin acts by binding to ovarian IGF receptors. Or the signaling system of high insulin-induced ovarian-derived hyperandrogen production is different from that of insulin-promoted glucose transport.
Abnormal growth hormone (GH) axis function
Human follicles and corpus luteum have expression of GH receptor gene. GH mediates through GH receptor or IGF-I receptor and has the effect of amplifying LH-induced androgen synthesis in vesicular cells and FSH-induced E2 and IGF-II synthesis in granulosa cells, suggesting that GH and IGF-1 are Gn-promoting substances (co-gonadotropin). However, human GH and IGF-1 are not absolutely necessary for follicular development, because patients with Laron type dwarfism caused by IGF-1 deficiency due to GH receptor abnormalities can still get pregnant spontaneously.
The mean amplitude of 24-hour GH pulse secretion is increased by 30% in non-obese women with PCOS. GH mediates IGF-1 in granulosa
The action of GH-mediated IGF-1 in granulosa cells is blocked by the presence of local inhibitory substances of FSH. However, GH-stimulated IGF-1 production acts via paracrine secretion in vesicle-mesenchymal cells, synergizing with LH to increase A2 production. Thus, high GH and concomitant high IGF-1, in concert with high LH, becomes one of the links in the pathogenesis of non-obese PCOS patients. In contrast, obese normal women and women with PCOS show a low growth hormone state, with a 50% reduction in 24-hour GH pulse amplitude, mean GH levels, and GH response to GHRH and L-DA. However, obese women with hyperinsulinemia and low GH inhibit lipolysis, making them even more obese.
Abnormal fat metabolism.
About 40% of PCOS patients have visceral obesity, elevated blood TG and reduced HDL-C. Some studies have shown that PCOS patients, with or without obesity, have abdominal subcutaneous fat that is resistant to catecholamines and has reduced lipolysis; conversely, visceral lipolysis is increased, causing an increase in free fatty acids, which in turn increases insulin resistance. The role of some new adipose hormones or cytokines in the pathogenesis is unclear.
(iii) Abnormal adrenocortical function
In the first 2 years of puberty, the weight of adrenal glands and cortical thickness increase, and the synthesis and secretion of adrenal androgens increase, which is clinically manifested by elevated blood DHEA and DS levels, reaching a peak at the age of 20-30 years, called the first appearance of adrenal function. The mechanism may be a local selective increase in 17,20 carbon chain enzyme activity in the adrenal glands, while 17α hydroxylase activity is not enhanced.
Serum DHEA and DS levels have been found to be elevated in 50-60% of PCOS patients and can be inhibited by dexamethasone (DEX) and stimulated by ACTH. Two types of abnormal adrenal function have been identified in patients with PCOS: (1) hyperfunction of cytochrome P450C17α enzyme, 17,20 carbon chain enzyme. (2) Hypersensitivity of adrenal androgens to normal levels of ACTH. This is similar to the initial changes in adrenal function. The cause of the abnormal adrenal function in PCOS is still unknown. It is thought that the hyperandrogenic state and hyperestrogenic (E1) state of PCOS affect the microenvironment in the adrenal glands and alter enzyme activity. Excessive adrenal androgens also affect the intra-ovarian microenvironment and cause excessive ovarian androgen production.
[Pathogenesis]
(a) Initial hyperadrenal function
(ii) Abnormal hypothalamic GnRH pulse generator
(iii) Promoter of extra-ovarian Gn (Co-gonadotropin): Poretsky (1994) studied the effects of insulin, HCG, and insulin plus HCG injection on ovarian morphology in rats and found that after insulin alone, although insulin levels were elevated, ovaries were unchanged; with HCG alone, ovaries were slightly enlarged and small cysts were formed; with insulin plus HCG, it caused The use of insulin plus HCG caused PCO and anovulation. The above suggests that high INS and high LH are two independent primary factors that act synergistically with the development of PCOS.
(iv) Genetic and environmental factors: PCOS patients have family clusters, and family lineage analysis has led to the conclusion of different genetic patterns such as autosomal dominant and X-linked dominant. Hyperandrogenemia and/or hyperinsulinemia may be the genetic phenotype of the disease in PCOS family members. Experimental studies have also shown that a genetic background can exist in PCOS with hyperactive ovarian and adrenal cytochrome P450c17α enzymes, abnormal post-insulin receptor signaling pathways and abnormal hypothalamic GnRH/LH pulse generators. No specific PCOS genes have been identified to date, but PCOS-related genes have been reported, and PCOS is more like the result of the action of multiple genes. Environmental factors are also associated with the development of PCOS, with anovulation and polycystic ovaries occurring in adulthood in female rats exposed to a hyperandrogenic environment during pregnancy. Ovarian hyperandrogenism in obese p hirsute women with PCOS is associated with excess weight at birth and maternal obesity.
[Diagnosis and differential diagnosis]
The 2003 meeting of experts from the American and European Reproductive Societies concluded that the diagnostic criteria for PCOS are hyperandrogenism, abnormal ovulation, and PCO on ultrasound, with the exception of other causes of hyperandrogenemia.
Diseases that must be differentiated include. Cortisolism (Cushing’s syndrome), congenital adrenocortical hyperplasia, 21 hydroxylase deficiency, androgen-secreting tumors of the ovary, hyperprolactinemia, thyroid abnormalities, idiopathic hirsutism, and pharmacologic hyperandrogenism.
[Treatment].
Adjustment of menstrual cycle to prevent endometrial hyperplasia and cancer.
Progesterone: MPA 6mg/d for 10 days on day 16-19 of the cycle may be used, stopping and waiting for withdrawal bleeding; for treatment of endometrial hyperplasia: simple or compound hyperplasia then MPA may be increased to 10mg/d for 10 days. The course of treatment is long and can be intermittent. In atypical hyperplasia, the treatment plan should be decided according to the requirements of the severity of the lesion. More potent progestins such as levonorgestrel 2-4mg/d and progesterone caproate 500mg/week are available. If the progesterone test is negative, it is combined with estrogen in sequence to induce artificial menstruation.
Oral contraceptives containing estrogen help to elevate SHBG and reduce the free T component. Mafron (marvelon) contains 30 μg of ethinyl estradiol and 150 μg of disoproxil per tablet, and compounded cyproterone (CPA, trade name Daing-35): 35 μg of ethinyl estradiol and 2 mg of CPA per tablet. However, long-term use should be monitored for metabolic and coagulation indicators.
Treatment of obesity and insulin resistance
Weight reduction: 1, diet control low calorie, low sugar, fat diet. 2, physical exercise: long-term adherence, lasting more than half an hour a day, is also beneficial to the prevention of cardiovascular disease risk.
Insulin sensitizers.
1 Metformin (metformin): pharmacological effects are (1) inhibit hepatic glycogen isogenesis and hepatic glucose output. (2) Improve the uptake and utilization of glucose by peripheral tissues and reduce blood insulin level without affecting insulin secretion, which can reduce hyperglycemia but not normal blood glucose. (3) Directly inhibit the production of androgens in human ovarian vesicle cells. Metformin treatment of obese and non-obese PCOS patients have placebo-controlled study results show: metformin group blood insulin levels decreased. gnRHa-stimulated LH, A production decreased. Menstruation, ovulation resumed, and even pregnancy. Blood LH and LH/FSH ratio decreased and FSH increased. Total testosterone, free testosterone, androstenedione decreased. SHBG, IGFBP-1 increased. The success rate was much higher in the placebo group when metformin was given for 1 month followed by ovulation promotion with chlordiazepoxide. This drug is a class B drug. However, there is a lack of information on the safety of early human pregnancy. Metformin may also correct dyslipidemia, have some hypotensive effects, reduce blood PAI-1 levels, and has inconsistent reports of effects on body weight. Side effects include anorexia, diarrhea, nausea, and epigastric discomfort, which are generally mild and can be alleviated by taking it before or during a meal. It does not generally cause hypoglycemia. For serum creatinine higher than 15mg / L, heart failure, diabetic acidosis, liver and kidney disease patients with caution.
2. Thiazolidinediones: They are highly selective and powerful agonists of peroxisome proliferation-activated receptor (PPARg), which can improve insulin sensitivity by binding PPARg and causing transcription of various genes related to the regulation of insulin effect. There is rosiglitazone (trade name Vindia), and it has been reported that PCOS patients taking rosiglitazone 4mg/day orally have resumed menstruation, improved insulin sensitivity, and decreased total T and FT after 2 months; pregnancy and successful delivery after 5 months. Rosiglitazone is not indicated for patients with poor hepatic function, type II diabetes or acidosis, or edema with poor cardiac function. It is a class C drug and can delay fetal development in animal studies; therefore, it is not recommended for pregnant and lactating women and patients under 18 years of age. Adverse effects include mild-moderate anemia and edema, and it is not recommended to be combined with metformin.
Although the above effects of insulin sensitizers are encouraging, multicenter prospective randomized controlled studies with larger samples are still needed to further confirm their efficacy, indications and safety before recommending them as first-line clinical treatment.
Fertility promotion: omitted
Treatment of hirsutism and acne
Treatment is not always necessary for mild hirsutism that does not interfere with ovulation or menstruation, but is often requested for psychological and cosmetic reasons when hirsutism is severe in patients with PCOS. Treatment of hirsutism requires at least 6 months to be effective. Long-term medication should be used to prevent drug side effects.
*Androgen receptor antagonists.
Acetocycloprogesterone (CPA): paired with estrogen, i.e. Daine-35. Ethinylestradiol inhibits skin 5 alpha reductase and elevates SHBG, making the treatment more effective. Daine-35 can be used to treat hyperandrogenemia and hirsutism, and also has a contraceptive effect. Acne has been reported to disappear after 3 months of treatment with Daine-35. Hirsutism may disappear or be reduced with long-term use of the drug. Ovarian volume was reduced and the number of small follicles per ovary decreased. Blood LH, FSH, E1, E2, T, A2, and DS decreased, SHBG increased, and INS, PRL, glucose, liver and kidney function were unchanged. However, long-term application should pay attention to the effects on glucose metabolism, blood lipids, and liver function.
Spironolactone (Androstadienone) is an aldosterone antagonist and diuretic, and an anti-androgen drug. It can be taken orally once a day. Most patients require 50-100 mg/d. It is contraindicated in renal insufficiency and hyperkalemia. Blood pressure and electrolytes must be monitored from low dose onwards and for the first 1-2 weeks of each dose to prevent hyperkalemia and hyponatremia. PCOS patients with amenorrhea or scanty menstruation may see a return to normal menstruation, and a few may see a decrease in LH, but generally there is no change in serum testosterone, dihydrotestosterone, androstenedione, and DS. Contraception should be used during the use of the drug to avoid affecting the development of fetal reproductive organs. It is generally recommended to be taken together with oral contraceptives to increase the efficacy on hirsutism.
Physical therapy: There is the use of the alexandrite laser (PhotogenicaApogee40T10 laser machine) with a wavelength of 755um, which acts to destroy the hair follicles for the purpose of treating hirsutism. The treatment must be carried out in stages when the hirsutism is extensive. The irradiation time is one ten millionth of a second, so the skin does not leave scars.
Prevention of Long-term Complications
PCOS patients with prolonged anovulation should adhere to oral contraceptives, or cyclic progesterone for withdrawal bleeding, and regular ultrasound measurement of endometrial thickness to prevent endometrial hyperplasia or cancer. The application of ovulation-promoting drugs should not be excessive. Control the diet and adhere to the exercise suitable for the individual. Prevent caloric excess and obesity. Urine glucose and blood sugar should be tested in obese patients to prevent the occurrence of type II diabetes.
Prevention of abnormal youth development and menstrual disorders?
Maternal health care during pregnancy and delivery: pay attention to nutrition, regular rules prenatal checkups and prevention of obstructed labor. Avoid taking medication as much as possible and perform necessary eugenic screening.
General health care: reasonable diet, proper exercise, appropriate weight control, no blind weight loss. Combine work and rest, and maintain a cheerful and optimistic mental state. Use special skin care products for children. Do not consume supplements or health products at will.
Menstrual hygiene: strictly prohibit sexual intercourse, tub bathing and swimming; clean sanitary napkins, change them regularly; wash the vulva regularly; eat less cold and raw food; pay attention to rest, avoid strenuous exercise and heavy physical labor; oppose sexual promiscuity and unclean sex; strictly contraceptive, avoid unplanned pregnancy and abortion.