It is the most common cause of anovulatory hyperandrogenism in women of reproductive age.
• Its incidence is 5-10% and it is a familial disease (multigenic) with complex hereditary features. It is characterized by clinical or biochemical hyperandrogenism, chronic anovulation and ultrasonographic polycystic ovary appearance. It is often associated with obesity and insulin resistance. It can have reproductive, metabolic and cardiovascular consequences.
pathophysiology PCOS
• The most important reason for the development of PCOS is chronic anovulation. In chronic anovulatory patients, central opiate tone decreases due to the absence of progesterone. As a result, the frequency of GnRH pulsatile oscillations increases. Increasing the GnRH pulsatile oscillation frequency increases LH release but not FSH release. The reason why FSH does not increase is due to the negative feedback effect of increased peripheral estrogens and the effect of normal levels of inhibin. Therefore, the LH:FSH ratio is increased in PCOS.
• Increased LH increases ovarian androgen production. Rising androgens suppress SHBG and increase the amount of free androgens. This leads to follicular atresia, anovulation, and hirsutism.
• Androstenedione, the level of which increases in the circulation, aromatizes in the periphery and increases the level of El. As a result, the E1:E2 ratio will also increase. Hyperestrogenemic environment not met with progesterone increases the risk of endometrial hyperplasia and endometrial cancer.
• Most of the PCOS cases have genetic autophosphorylation defects in insulin and CYP17 enzyme receptors (serine autophosphorylation instead of tyrosine autophosphorylation). As a result, hyperactivity and insulin resistance occur in p450c17 enzymes.
► Due to the hyperactivity of the p450c17 enzyme, an increase in adrenal androgen (DHEA-S) production is also observed in approximately half of the patients with PCOS. Thus, androgen production increases in both the adrenals and the ovaries.
► Failure of the insulin receptor causes insulin resistance and hyperinsulinemia. PCOS patients with insulin resistance and associated hyperinsulinemia are mostly obese. Insulin resistance is correlated with the risk of cardiovascular disease in patients with PCOS.
Tests Used in the Diagnosis of Insulin Resistance
1. Fasting glucose/insulin ratio; < 4.5 indicates insulin resistance
2. Two hour 75 gram oral glucose tolerance test; Insulin levels are measured 2 hours after a 75-gram glucose load. peak value
If > 150 µU/ml or the average of 3 values > 84 µU/ml, it indicates insulin resistance.
3. HOMA-IR (Homeostasis Model of Assessment - Insulin Resistance); Fasting insulin is calculated with the formula µU/ml x fasting glucose mmol/L / 22.5 and the normal value is < 2.77.
4. Fasting serum insulin level
5. QUICKI {The quantitative insulin sensitivity check index); 1/[log fasting insulin(µU/mL) + log fasting glucose (mg/dL)]. The normal value is > 0.357.
6. Hyperinsulinemic euglycemic clamp test; It is the gold standard method for determining peripheral insulin resistance.
• Although insulin resistance is often associated with hyperandrogenism, it is completely independent of it. Insulin increases steroid production in the ovaries independently of gonadotropin secretion. Insulin and IGF-I receptors are found in the ovarian stromal cells. SHBG and IGF-BP levels decrease in hyperinsulinemia. As a result, free steroid hormones increase and with the effect of increasing IGF, androgen production from the ovary increases.
• The coexistence of hyperandrogenemia and insulin resistance in patients is called HA-IR syndrome. In cases where insulin resistance and hyperinsulinemia are more severe, due to the mitogenic effect of insulin on the basal cells of the epidermis, hyperpigmentation occurs in some skin areas (most commonly vulva, axilla, nape, under the breast, inner thigh) (acanthosis nigricans). It is called HAIR-AN syndrome
• Hyperprolactinemia is observed in approximately 25% of patients with PCOS. In these cases, the use of bromocriptine improves ovarian functions by decreasing the LH level.
Short-term results in polycystic ovary syndrome
1. Obesity
2. Infertility
3. Menstrual irregularities
4. Abnormal lipid levels
5. Hirsutism / acne / androgenic alopecia
6. Glucose intolerance / acanthosis nigricans
7. Sleep apnea
8. Non-alcoholic fatty liver disease
9. Depression and mood disorder
Long-term complications in polycystic ovary syndrome
1. Diabetes mellitus
2. Dyslipidemia (hypercholesterolemia, hypertriglyceridemia)
3. Coronary heart diseases
4. Hypertension
5. Endometrial cancer
6. Ovarian cancer
7. If the patient becomes pregnant, abortion and Intrauterine growth retardation
Clinic PCOS
• Oligomenorrhea-amenorrhea: Amenorrhea occurs rather than irregular bleeding.
• Hirsutism (70%)
• Obesity (50%): There is android (central) obesity and the waist-to-hip ratio has increased (>0.85). Obese PCOS patients have a high risk of cardiovascular disease and DM.
Diagnosis PCOS
• Although there is no consensus regarding the diagnosis of PCOS, one of the following two diagnostic criteria can be preferred in addition to exclusion of other causes of hyperandrogenemia.
► Presence of both of the following two criteria;
0 Hyperandrogenism; Clinical (hirsutism) and/or biochemical (hyperandrogenemia)
0 Ovarian dysfunction; Oligoanovulation and/or polycystic ovary image
► Presence of at least two of the following three criteria;
0 Hyperandrogenism; Clinical (hirsutism) and/or biochemical (hyperandrogenemia)
0 Oligoanovulation
0 Polycystic ovary image
• Polycystic ovary image: Each ovary should have 12 follicles, 2-9 mm in diameter, and/or ovarian volume should increase (> 10 ml). Macroscopically, the ovaries enlarged 2-5 times their normal size and increased in volume. It is seen in 23% of women of reproductive age. PCOS with polycystic ovary appearance is not associated with an increased risk of cardiovascular disease, independent of BMI, age, and insulin resistance.
• According to these diagnostic criteria, late-onset adrenal hyperplasia, adrenal and ovarian functional tumors, Cushing's syndrome, hypogonadotropic or hypergonadotropic anovulation, hyperprolactinemia, thyroid pathologies and acromegaly that cause the PCOS phenotype should be excluded.
Lab PCOS
• The ratio of LH:FSH increases (3:1).
• Androstenedione and testosterone levels increase.
• E1: E2 ratio increases.
• In 50% of cases, the DHEA-S level rises to the upper level of baseline.
• Prolactin level increases in 25% of cases.
• Insulin resistance may accompany.
• Total cholesterol, triglyceride and LDL increase; HDL and apoprotein Al are reduced (the most characteristic change is HDL2alpha reduction).
• SHBG decreases.
• Plasminogen activator inhibitor increases; fibrinolysis is impaired.
• Antimullerian hormone level increases.
Treatment PCOS
• Most of the treatments recommended in PCOS are symptomatic treatments and aim to protect the patient from the long-term undesirable effects of chronic anovulation.
• The primary treatment in obese patients is lifestyle changes (weight loss, exercise). It is recommended that obese patients (BMI>30) lose 5-10% of weight in 6-12 months. In this case, insulin resistance and peripheral transformation will decrease and the vicious cycle of anovulation will be broken. With weight loss, abnormal glucose metabolism may improve, ovulatory function may improve (75%), and hyperandrogenism may decrease. Losing 10 kg reduces insulin levels by 40% and testosterone levels by 35%. Planned exercise (>30 min/day) reduces insulin resistance regardless of weight.
• In patients who do not want pregnancy, hormonal suppression is applied with COCs. However, ovulation induction should be performed in patients who want pregnancy.
• Insulin sensitizing agents (metformin) are used in patients with insulin resistance.
Treatment in PCOS
Ovulation induction for infertility treatment; Letrozole, clomiphene citrate (metformin may be added), gonadotropins, ovarian drilling, invitrofertilization (IVF)
Treatment of abnormal uterine bleeding; Cyclic progesterone, combined oral contraceptive
· Treatment of skin manifestations; Combined oral contraceptive + antiandrogen (spironolactone, finasteride), GnRH agonists
Obesity and metabolic status; Diet, lifestyle changes, metformin
Clomiphene citrate (CC) or letrozole is the first line treatment for ovulation induction in anovulatory infertility.
Insulin sensitizing agents
Metformin
0 It is an oral antihyperglycemic (biguanide) agent. Primary effect; to decrease glucose production by inhibiting gluconeogenesis in the liver, to decrease glucose absorption from the intestine and to increase peripheral glucose uptake by increasing the sensitivity of the target tissue to insulin (postreceptor effect). After 12 weeks of treatment in obese PCOS cases, fasting insulin, LH, free testosterone and endothelin-1 levels are reduced.
0 Metformin increases ovulation rates, alone or in combination with CC, in insulin-resistant obese PCOS patients. It is a serious alternative to CC, especially in resistant anovulatory cases. In patients with PCOS receiving metformin + clomiphene, ovulation is higher than when clomiphene or metformin is given alone.
0 Incidence decreases with the use of adjuvant metformin in women with PCOS who are at serious risk of OHSS.
Thiazolidinediones
0 This group includes troglitazone, pioglitazone and rosiglitazone. It is used to increase insulin sensitivity and decrease androgen levels in PCOS.
Ovarian drilling
0 Spontaneous ovulation developed in 75% of PCOS cases as a result of laparoscopic drilling with electrocautery (drilling), and pregnancy developed in 72% of these cases within 2 years. This process both decreases ovarian androgens and decreases LH levels while increasing FSH concentration. It is used in clomiphene-resistant PCOS. The most obvious side effect is the adhesions that may occur after the procedure.