I. Reproductive endocrine in adolescence
From the physiological point of view, the endocrine status of adolescence is mainly manifested as follows.
(1) The function of hypothalamus-pituitary-ovarian gonadal axis is not perfect during puberty, and the positive feedback effect of hypothalamus and pituitary gland on estrogen is defective, so the cycle is mostly anovulatory 1-3 years after menarche. Cao Xiaoju, Department of Traditional Chinese Medicine, Hospital
(2) Increased synthesis of androgens by the adrenal glands and ovaries, resulting in physiological hyperandrogenemia, acne and the growth of pubic and axillary hair.
(3) Decreased insulin sensitivity of body tissues during pubertal development, resulting in physiological insulin resistance and hyperinsulinemia.
(4) Multiple follicular ovaries are often seen on ultrasound in normal adolescent girls, with a gradual decrease in small follicles as ovulation is established and perfected.
(5) The frequency and amplitude of gonadotropin-releasing hormone pulse secretion increases during puberty, LH secretion increases, and the wake-sleep difference disappears, resulting in a change in the LH/FSH ratio from <1 to >1.
Second, the differentiation of pubertal PCOS and pubertal physiological changes
Adolescent PCOS needs to be differentiated from congenital adrenocortical hyperplasia, Cushing’s syndrome, and androgen-secreting tumors and other diseases. It is important to note that there are many similarities in the clinical manifestations of normal pubertal physiological changes and pubertal PCOS, and how to distinguish between the two is important for the early diagnosis and treatment of patients with pubertal PCOS. It has been suggested that early screening for PCOS is necessary for adolescent girls with the following conditions.
(1) Hirsutism or acne with irregular menstruation or obesity.
(2) Severe acne that requires treatment in early adolescence or that has failed to respond to treatment with conventional methods.
(3) Failure to establish a normal menstrual cycle 2 years after menarche.
(4) Excessive weight gain during adolescence with acanthosis nigricans, and/or a family history of metabolic syndrome or type 2 diabetes mellitus.
Third, theories related to the pathogenesis of adolescent PCOS
PCOS may be a continuation and expansion of adolescence and may develop due to abnormal initiation and hyperdevelopment of adolescence, which can be called “hyperpubertal” or “hyperpubertal” phenomenon, the main cause of which is adolescent Physiological insulin resistance develops into pathological insulin resistance for some reason and/or persists into adulthood, becoming the central link in the pathogenesis of PCOS. Insulin is one of the hormones necessary for growth and development during puberty. The decrease in insulin sensitivity of body tissues during puberty and the emergence of physiological insulin resistance mainly affect the glucose metabolism of peripheral tissues, causing a compensatory increase in insulin secretion and hyperinsulinemia. Physiological insulin resistance in adolescence is necessary for the normal growth and development of the body. When there is some reason for excessive increase of insulin level in puberty, excessive increase of androgen and IGF-1 level and enhanced ovarian response to gonadotropin cause dysregulation of insulin/IGF-1 system, thus insulin resistance persists and becomes a pathological state, which in addition to affecting glucose metabolism of peripheral tissues, also makes skeletal muscle and adipose tissue less sensitive to insulin, and may induce PCO.
2 Genetic theory
The clinical manifestations and symptoms of PCOS are highly heterogeneous and change from time to time; its pathophysiology also shows that PCOS is multifactorial and multi-causal, and the heterogeneity of PCO clinical manifestations may be caused by different genetic mechanisms.
3. Fetal origin theory
Dr. Barker proposed in the late 1980s. This hypothesis suggests that the fetal response to intrauterine malnutrition causes adaptive regulation of its own metabolism and organ architecture, and if malnutrition is not corrected in time, this adaptive regulation will lead to permanent changes in the metabolic patterns of body tissues and organs, including blood vessels, pancreas, liver and lungs, which will evolve into adult-onset disease. This long “programmed” change can be amplified by many acquired environmental factors that enhance and accelerate the development of adult disease. Intrauterine malnutrition can lead to fetal growth retardation and low birth weight, and affect the fetal metabolic and hormonal environment to ensure survival, and this adaptive change can continue after birth and lead to greater insulin secretion for greater weight gain in order to catch up with growth.
IV. Clinical features of adolescent PCOS
Because of the similarities between the physiological changes during puberty and the pathophysiological aspects of adolescent PCOS, understanding the clinical features of adolescent PCOS patients can help distinguish normal adolescent females from those with adolescent PCOS.
1 . Menstrual pattern: normal adolescent girls will have regular ovulatory menstruation 2 years after menarche, 12% of girls will have sporadic menstruation at the age of 18, 5l% of sporadic menstruation cannot be reversed leading to PCOS, the persistence of this menstrual abnormality is mainly related to excessive weight gain, elevated LH and androgens, etc. Domestic study found that only 23.1% of normal pubertal controls had menstrual abnormalities, and all were sporadic, while the incidence of menstrual abnormalities in 58 cases of pubertal PCOS patients increased significantly to 87.9%, in addition to 55.2% for sporadic menstruation, there were 20.7% amenorrhea and 12.1% menstrual disorders, from the age grouping of pubertal PCOS, menstrual abnormalities in the middle and late pubertal groups In the age group of adolescent PCOS, menstrual abnormalities in the mid-adolescent and late adolescent groups are mainly menstrual sporadic, accounting for more than 40%, and amenorrhea accounts for about 20%
2. hairy, acne: normal adolescent women show signs such as hairy, acne, etc., only 3.8% of the hairy, not as obvious as PCOS patients, and with the transition to adulthood, its signs gradually reduced, acne is mainly scattered in the face, hair is mainly distributed in the pubic hair, axillary hair and other parts. The hyperandrogenemia in adolescent PCOS patients does not disappear with the transition from puberty to adulthood. It is suggested that we should pay high attention to adolescent girls with both hirsutism and menstrual disorders during puberty and, if necessary, conduct a detailed and comprehensive examination to exclude pubertal PCOS.
3. obesity: is also a common clinical manifestation of PCOS, and often male obesity (waist circumference / hip > 10.85). the incidence of obesity in patients with PCOS is about 50%, mostly in adolescence. Obesity is more severe in PCOS patients with androgen excess and insulin resistance.
The difference between follicular ovaries and polycystic ovaries in normal adolescent girls is that the former have 6-10 follicles, 4-10 mm in diameter, normal ovarian stromal echogenicity, and a smaller total volume. In adolescent PCOS patients, multiple ovarian follicles (more than 10 follicles unilaterally) with enhanced interstitial echogenicity and increased volume (>10m1) are seen on ultrasound. This indicates that the increase in ovarian volume as a feature of adolescent PCOS can be well differentiated between adolescent PCOS and normal ovaries. The specificity and sensitivity of the diagnosis of pubertal PCOS by the number of follicles ≥11 in a single ovary was >85%. The combination of ovarian volume and follicle number to diagnose pubertal PCOS had a higher specificity (96.2%), but its sensitivity was lower (77.3%).
5. Insulin resistance and abnormal glucose tolerance: Adolescent PCOS patients not only have insulin resistance, but most of them also have abnormal glucose tolerance, and Lu Xiang et al. reported that the incidence of low glucose tolerance in adolescent PCOS was 24.1%, and it was as high as 40% in the insulin resistance group. The prevalence of insulin resistance in adolescent PCOS was 33.5% in the endocrine outpatients of the Obstetrics and Gynecology Hospital of Fudan University, and the degree of IR was aggravated by obesity. In the second hospital of Sun Yat-sen University, the incidence of insulin resistance in PCOS patients with adolescent onset was 25.5%, and the incidence of insulin resistance in obese patients (BMI ≥ 24 kg/m) was higher than that in non-obese patients, and there was a significant difference between the two.
6. Biochemical indicators: there were also significant changes compared to normal controls, such as luteinizing hormone (LH) levels and LH/FSH ratio. Our study showed that LH was negatively correlated with body weight, obesity may inhibit hypothalamic GnRH pulse frequency or pituitary LH responsiveness, and the negative correlation between LH and BMI may be related to the distribution and volume of adipose tissue. Moreover, IH levels, LH/FSH were higher in obese PCOS patients than in controls, suggesting that these two indicators may be independent factors associated with PCOS in Chinese PCOS patients. LH levels, LH/FSH were significantly higher in patients with lean body type than in overweight patients, and LH levels were elevated in 76.27% of PCOS patients.
V. Diagnosis of adolescent PCOS
There are no recognized diagnostic criteria specifically for adolescent PCOS, some experts have proposed the following suggested criteria for the diagnosis of adolescent PCOS, in fact, based on the Rotterdam diagnostic criteria to include indicators of metabolic abnormalities, in order to highlight the importance of metabolic abnormalities in the early diagnosis and treatment, the researchers suggest that adolescent PCOS can be diagnosed when any two of the following three items are present (1) within 2 years of menarche
(i) failure to establish regular menstrual cycles within 2 years after menarche and development of clinical manifestations of menstrual disorders such as scanty menstruation or amenorrhea.
② Androgen levels above the upper limit of physiologically defined values and/or with moderately severe, recurrent acne.
(3) Ovaries with morphological changes that meet the Rotterdam diagnostic criteria, again with other hyperandrogenic disorders yet to be excluded.
Adolescent PCOS: (1) transabdominal ultrasound is inaccurate for detection of the ovaries; (2) clinical features are preferred; (3) pelvic ultrasound (transrectal ultrasound) should be chosen.
The diagnosis of PCOS in adolescence should not exactly follow the criteria for adults. It has been proposed that insulin resistance-related indicators should be considered for inclusion in the diagnostic criteria and become an important basis for the development of treatment plans.
The diagnosis of adolescent PCOS, like adult PCOS, is a diagnosis of exclusion, and care must be taken to exclude associated diseases before considering PCOS.
Sixth, about screening
In view of the characteristics of the onset of adolescent PCOS, it has been proposed that adolescents with irregular menstruation 2 to 3 years after menarche should be screened for PCOS if they have the following high-risk factors.
(1) Family history (PCOS, male pattern baldness, diabetes, hypertension, obesity).
(2) Obesity before puberty.
(3) Restricted growth in the fetus, rapid growth after birth, or high birth weight.
(4) Early onset of adrenal cortical function or early appearance of pubic hair.
(5) Early onset of menstruation.
(6) Overweight or obesity.
(7) Persistent anovulation.
(8) Hyperandrogenemia.
(9) Metabolic syndrome.
(10) Hyperinsulinemia in different disease conditions, including genetic defects of insulin receptors, genetic defects of congenital lipid nutritional disorders, receiving high-dose oral glucose therapy due to glycogen accumulation disease and having type 1 diabetes.
VII. Treatment concept of adolescent PCOS and evaluation of related drugs
The treatment concept: With the understanding of the pathogenesis of PCOS and the emphasis on the detection of endocrine and metabolic abnormalities, early intervention in PCOS is advocated, and the treatment is individualized for different endocrine characteristics and disease periods, as well as for the needs of the patient. The immediate goals are to regulate the menstrual cycle, control hirsutism, acne and weight, and correct endocrine and metabolic abnormalities. Long-term goals are prevention of diabetes, endometrial hyperplasia, obesity, heart disease and infertility.
Specific measures include, among others
Lifestyle modification; including diet modification and exercise, weight reduction
Correction of endocrine and metabolic abnormalities: both treatment of hyperandrogenemia and control of disorders of glucose and lipid metabolism, as well as attention to the effects of drug side effects on metabolism and development.
Treatment of insulin resistance.
Ovulation promotion therapy.
It is also not possible to distinguish between those who have sporadic menstruation as PCOS and those who recover on their own. The diagnosis of PCOS should not be made in the case of regular menstruation with suspected PCOS symptoms. However, the absence of a diagnosis does not mean the absence of treatment.
Interventions are based on clinical signs and symptoms, which, even if not PCOS, can have serious health consequences for adolescent women.
Menstrual disorders – anovulatory uterine bleeding
Kaohsiung – body aesthetics
Obesity – metabolic syndrome
Patients with obesity and metabolic syndrome should be treated regardless of the diagnosis of PCOS.
If obesity and insulin resistance exist in adolescence, treatment and correction of this problem is a priority.
2. Drugs
2.1. Oral contraceptives (Ocs).
OCs inhibit ovarian-derived androgens in addition to several anti-androgenic mechanisms, including: inhibition of gonadotropin overproduction, inhibition of adrenal-derived androgen overproduction, inhibition of IGF2 action, and reduction of androgenic activity by increasing SHBG concentrations and competition for androgen receptors on target organs. The effectiveness of OCs in reducing testosterone, androstenedione and LH/FSH ratios after 3 cycles of dosing and improving hirsutism and acne after cycle 6 has been well established.
Minor adverse effects, including mild weight gain due to sodium retention, breast tenderness and mood changes, and serious adverse effects such as venous thromboembolism, are rare in young adults.
1) Marvelon, manufactured by Oganon in the Netherlands, contains 0.030 mg of EE and 0.150 mg of deprenyl, which has a stronger inhibitory effect on LH, so that the LH/FSH value decreases after marvelon treatment, breaking the vicious cycle between LH and hyperandrogenism and reducing ovarian androgen production, which is the basis of deprenyl treatment for hyperandrogenemia.
(2) Yasmin, manufactured by Schering in Germany, contains Drospirenone 3mg and EE 0.030mg, which can improve androgenic symptoms such as acne, seborrheic dermatitis, etc. OC containing Drospirenone can reduce androgen levels, but has no effect on weight gain.
(3) Daing 35: CPA2mg and EE 0.035, cyproterone acetate (CPA) is a synthetic derivative of 17 hydroxyprogesterone, a potent progestin with prominent anti-androgen effects. It can compete with T for receptors, and the resulting cyproterone-androgen receptor complex can also enter the nucleus without producing androgenic effects, thus blocking androgenic effects. It decreases 5a-reductase activity and thus inhibits the effects of T and DHT. It also induces enzymatic activity in the liver to increase the clearance of T. It inhibits the secretion of gonadotropins because it is itself a progestin, thus reducing the production of T and A by the ovaries. It can be used for 4-6 cycles after the height has been largely determined.
2.2. Drugs that inhibit androgenic effects.
These include cyproterone, flutamide, and androstadienone, as well as 5-monoreductase inhibitors such as finasteride.
Flutamide is a purely anti-androgenic drug, mainly acting on androgen receptors, 250 mg per day, alone or in combination with OC, can be used significantly.
or in combination with OC can significantly improve hirsutism and acne in patients with PCOS.
In recent years, insulin sensitizers have been increasingly used because of their endocrine and metabolic therapeutic effects on PCOS patients.
In recent years, as insulin sensitizers can have endocrine and metabolic therapeutic effects on PCOS patients, they are increasingly used, mainly metformin and thiazolidinediones such as rosiglitazone. In recent years, metformin has also been used in adolescent PCOS, and although it has been reported less frequently and with shorter follow-up, all available data show that it improves the menstrual cycle, restores dilation, and reduces body mass in adolescent girls on a low-calorie diet. Metformin treatment is well tolerated, with gastrointestinal discomfort and diarrhea occurring in only a small proportion of patients, and these symptoms are usually self-limiting and may disappear with gradual dose reduction.
The question of whether to use the drug earlier in a population at high risk for PCOS (low birth mass and precocious puberty) has also been investigated, and it was concluded that the prophylactic use of metformin in these patients during adolescence, various parameters such as SHBG, androstenedione, dehydroepiandrosterone (DHEAS), low-density lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol (HDLC) triacylglycerol, interleukin-6 (IL I-6), lipocalin, and total abdominal fat mass were improved, effectively reversing the development of their PCOS. However, once the drug was discontinued, all abnormal features were repeated.
There are still questions about the need for lifelong medication in adolescent PCOS patients, but the persistence of pathophysiologic changes in PCOS is certain. Therefore, regular review of the patient and adjustment of the treatment regimen as appropriate is necessary. The recurrence or even exacerbation of insulin resistance or hyperinsulinemia and hyperandrogenemia, two key pathological aspects of PCOS, have been reported in patients who discontinue treatment.
Experts believe that long-term but prudent, closely monitored treatment and follow-up are still necessary
PCOS goes beyond gynecologic endocrine disorders and is a group of chronic, multisystemic endocrine disorders with different risks of metabolic abnormalities in different PCOS subtypes, with hyperandrogenism being a risk factor for abnormal lipid metabolism. The cardiovascular and metabolic complications that result can persist, and gonorrhea can also have adverse health effects on adolescents during adolescence. Therefore, the potential long-term effects of these symptoms on metabolic and cardiovascular disease must be taken into account, and patients with suspected PCOS in adolescence should be treated and monitored closely over time to improve poor health outcomes and quality of life. Early intervention during adolescence can delay or even prevent the onset of many diseases in adulthood.
For the abnormal clinical manifestations of adolescence, it is not possible not to treat them because they are not diagnosed as PCOS, nor is it possible to misdiagnose the physiological characteristics of adolescence as PCOS, causing panic among patients and their families.
Eight, the idea and method of Chinese medicine treatment of adolescent PCOS
At present, the treatment of polycystic ovary syndrome by Chinese medicine is still in the stage of empirical treatment and academic exploration. Although the patient population in China is large, there are no evidence-based (multicenter, randomized, large sample) studies on polycystic ovary syndrome in adolescence from the perspective of TCM, which is a pity, and this current pity should therefore be the goal to motivate our efforts. The main principles of current TCM treatment for this disease are
1. menstrual disorders – tonifying the kidneys, draining the liver, strengthening the spleen, promoting the ripening of the tianji, and regulating the rheumatism
2. acne – clearing lung heat, lowering depressed fire, and clearing stagnation
3. ? Obstruction in the intestine–clearing phlegm stagnation and eliminating stasis
4. obesity-strengthening the spleen, resolving phlegm and dampness, and eliminating fat
Treatment methods are: evidence-based treatment/acupuncture treatment/ear point pressure bean.