PCOS: a syndrome of ovarian dysfunction.
Incidence 4-12% in women of reproductive age, highest incidence of endocrine disorders
Infertility, dysfunctional bleeding, endometrial cancer, obesity, type 2 diabetes, dyslipidemia, hypertension, possible cardiovascular disease
Sporadic ovulation and or non-ovulation
Clinical and or biochemical hyperandrogenism
Ovarian polycystic-like changes
Exclusion (congenital adrenocortical hyperplasia, androgen-secreting tumors, Cushing’s syndrome)
Sporadic or amenorrheic menstruation two years after menarche
Clinical hyperandrogenemia: persistent acne, hirsutism
Biochemical Kaohsiung: elevated testosterone, increased LH and LH/FSH ratio Biologic
Insulin resistance/hyperinsulinemia: acanthosis nigricans, abdominal obesity, impaired glucose tolerance
PCO-like changes: enlarged ovaries, increased number of small follicles, interstitial hyperplasia
Exact pathogenesis is unknown
Probably complex polygenic disorder with disordered gonadotropin release and dysregulated steroid hormone production
Hyperinsulinemia plays an important role in the pathogenesis of PCOS
Under normal conditions, GnRH pulses cause the release of LH and FSH
LH stimulates follicular membrane cells to synthesize androgens and FSH stimulates granulosa cells to convert androgens into estradiol and estrone
Under normal conditions there is a negative feedback from estrogen and progesterone to GnRH secreting neurons and pituitary gland. Increased LH levels and increased secretory pulses in adolescent PCOS patients
The disordered endocrine state may be more severe in obese adolescents
Increased number of follicular membrane cells and increased capacity for steroid hormone synthesis in PCOS patients
Functional ovarian hyperandrogenism due to high LH levels and insulin resistance. Insulin synergizes with LH to promote follicular membrane cell proliferation and increase androgen production. There was no significant increase in the expression level of aromatase in the granulosa cells of developmentally blocked follicles, which significantly decreased estrogen production; whereas the increase in the concentration of 5α-reductase enzyme in granulosa cells led to an increase in the expression level of 5α-androstane-3,17-dione, which is a competitive aromatase inhibitor that causes an increase in androgen levels. sensitivity of granulosa cells to LH, causing increased production of progesterone
Excessive androgens (DHEAS) may also be due to defective steroid hormone synthesis of adrenal origin, functional hyperandrogenemia of adrenal origin
Increased levels of ovarian or adrenal-derived androgens decrease hepatic levels of sex hormone-binding globulin, causing increased free testosterone levels
In insulin-resistant obese patients, SHBG is significantly lower and free testosterone is significantly higher
Alterations mainly around menstruation, with changes in the internal environment during puberty mainly due to weight gain
PCO-like alterations can be detected as early as 6 years of age in girls
Diagnosis is rather difficult before puberty, as menstrual disorders and associated skin changes do not appear before puberty
Sparse menstruation or secondary amenorrhea 12-24 months after menarche
LH, FSH, PRL, 17-OH, DHEAS measurements
Blood glucose, insulin measurement, OGTT
Menstrual & ovulatory dysfunction
Sporadic menses (cycles greater than 35 days, or less than 10 menses per year)
Frequent menstruation (cycle less than 25 days)
Amenorrhea (menopause of 3-6 months)
Abnormal uterine bleeding
Anovulation
75-85% have clinical signs of menstrual disorders, 20-30% of PCOS patients have normal menstruation despite the presence of anovulation and less than 2% have frequent menstruation
Primary amenorrhea is not a common manifestation in PCOS patients, and those with primary amenorrhea may have more severe hyperandrogenemia and metabolic disorders
Menstrual disorders may begin at menarche or may occur gradually with age, and some patients may have a regular menstrual cycle for a period after menarche
Clinical hyperandrogenemia
Hirsutism: 65C75% of patients with PCOS have signs of hirsutism, which can be scored using the Ferriman and Gallwey method.
Acne: 15C25% of patients with PCOS have this symptom
Androgenetic alopecia: thinning of hair from the crown to the anterior hairline is the only skin feature in PCOS patients, with 5-50% of patients showing hair loss
Biochemical hyperandrogenemia
Elevated free testosterone levels in 70% of adults and 25% of adolescents with PCOS
Elevated DHEA levels, which are stable during the menstrual cycle and on a daily basis, are the most abundant adrenal-derived androgens in serum and have a long half-life as a diagnostic indicator of elevated levels of adrenal-derived androgens
Polycystic ovaries
≥12 follicles of 2-9 mm on one or both sides
Ovarian volume >10 ml
It is unclear whether the adult PCO diagnostic criteria are appropriate for adolescents
PCO-like changes are present in 55% of adolescents and in only 10% of girls with regular menstruation
The severity of PCO-like changes correlates significantly with menstrual disorders, and 40% of girls with developmentally delayed follicles present with PCO-like subclinical manifestations and abnormal 17-OH progesterone response to GnRH.
Gonadotropic abnormalities
Gonadotropic abnormalities are present in 75% of patients
Elevated LH levels and increased LH/FSH ratio
Metabolic screen
Metabolic syndrome: dyslipidemia, obesity, abnormal glucose tolerance
Metabolic syndrome is present in 50-70% of patients
Metabolic syndrome is present in 12C44% of adolescents
Obesity is a strong predictor of metabolic syndrome
Impaired glucose tolerance and increased risk of type 2 diabetes
Metabolic screen
PCOS and hyperandrogenism are major risk factors for dyslipidemia
Approximately 50% of women with PCOS are obese
Obesity exacerbates the phenotype of PCOS
BMI is positively associated with androgen levels in adolescents and adults
Lower body weight reduces free testosterone levels and improves insulin sensitivity and ovulation
The high prevalence of obstructive sleep apnea in adult women with PCOS is not explained by obesity alone
The incidence of obstructive sleep apnea in adolescents with PCOS is not high
The incidence of obstructive sleep apnea may increase with the progression of PCOS
adrenal cortical hyperplasia
insulin resistance
Idiopathic hirsutism
Androgen-secreting tumors
Cushing’s syndrome, high PRL, abnormal thyroid function
Treatment
Lifestyle modification: The first effective treatment for adolescents with PCOS is to reduce body weight by 2-7%.
Reducing body weight by 2%-7% can significantly reduce androgen levels and improve ovulation. Limiting carbohydrate and fat intake and increasing aerobic exercise
Cosmetic treatment
Cosmetic use and electro-acupuncture
High pulse electro-acupuncture, 70% of patients satisfied at 2 years follow-up
Topical application of eflornithine hydrochloride for 6-9 months improved the symptoms of hirsutism.
Hormonal treatment
Eusebio: Trasylol 3mg, Ethinylestradiol 30ug
Duration of treatment: 1-2 years, the anti-androgenic effect can be maintained for about 2 years after stopping the drug
Affects insulin sensitivity, vascular reactivity and risk of hypercoagulable state
Hormonal treatment-ocp
Use with caution in migraine, use the ocp with the lowest estrogen content
No increase in body weight or fat content
Reduces testosterone and free testosterone index in adolescent patients, but increases C-reactive protein and cholesterol levels (risk of inflammatory response and lipid metabolism disorders)
OCP with cyproterone acetate (CPA) and deoxyprogesterone components may regulate cycles and reduce hirsutism, but increase insulin resistance, total cholesterol, LDL, HDL levels
Hormonal treatment-ocp
OCP with CPA component can cause higher triglyceride and cholesterol levels, increased insulin secretion and hyperinsulinemia
The use of OCP increases the risk of diabetes, especially in obese people with insulin resistance
Antiandrogens
CPA
Trazodone: inhibits ovarian and adrenal androgen production; blocks the binding of dihydrotestosterone to skin androgen receptors; increases SHBG levels; increases androgen clearance and decreases 5α reductase activity
Trazodone: starting dose, 100 mg/day for thin and hairy individuals; 200 or 300 mg/day for severely hairy or obese individuals
Antiandrogens
Side effects of trazodone: severe thirst, polyuria, nausea, headache, exertion, frequent menstruation
Aldosterone antagonist, diuretic effect, causes hyperkalemia (mainly seen in older individuals, adolescents are mainly at theoretical risk)
Reduce side effects, starting dose 25mg/day tapered for at least 6 months, maintenance dose 25-100mg/day, obese need to increase dose
Reduces total fat and improves acne
Antiandrogens
Flutamide (non-steroidal): hepatotoxicity
Non-obese hyperinsulinemic, hyperandrogenic young women: metformin, OCP, low dose pioglitazone and flutamide significantly improved cardiovascular status, treatment discontinued for two years, no significant complications and side effects seen
Finasteride (type 2 5 alpha reductase inhibitor) and eflornithine hydrochloride have been used to treat hirsutism
Insulin sensitizers
Metformin may be more effective in adolescents than in adults
Metformin may halt the progression of PCOS in specific populations, such as women born after a small gestational age with early onset of adrenal function
Metformin improves insulin levels, adjusts cycles, and for 6-12 months significantly reduces androgen and lipid levels and improves symptoms of hirsutism
The combination of metformin, lifestyle modification and OCP can reduce central obesity, total testosterone levels and increase HDL levels
In adolescent PCOS patients, metformin needs to be used for a long time, and the therapeutic effect disappears after 3 months of discontinuation
Spontaneous ovulation may occur during metformin use, reassessment of continued use is required in case of pregnancy, metformin may cross the placenta
Insulin sensitizers-Thiazolidinediones
Improves insulin action and increases glucose utilization in liver, skeletal muscle, and adipose tissue
Safety of use in adolescents needs to be evaluated
Combined with lifestyle modification
Alternative treatments
Acupuncture: Improves metabolic and endocrine function
Chinese herbal medicine: Tiangui Fang – reduces insulin levels and improves ovulation
Minerals – Chromium: modulates insulin action and improves lipid metabolism
Inositol: Improves insulin signaling pathways and restores normal ovulatory function
Surgery: laparoscopic ovarian ‘drilling’
Conclusion
PCOS is an endocrine disorder affecting adolescent and adult women
Early diagnosis and treatment are important to enhance self-confidence and prevent the onset of adult life
Treatment of adolescents: diet, exercise, metformin, trospium, OCP, with weight loss as the ultimate treatment goal for obese individuals
OCP is recommended for cycle adjustment to reduce androgens, tricyclomine for hirsutism, metformin to improve insulin sensitivity, and a healthy diet combined with regular exercise to improve symptoms and reduce long term complications.