1. In The Name Of God

2. PCOS

3. Polycystic ovarian syndrome (PCOS) is an extremely common disorder affecting 4% to 12% of women of reproductive age. Despite being heterogeneous in nature, the hallmarks of the disease are hyperandrogenism and chronic anovulation

4. Stein-Leventhal Syndrome
Stein I, Leventhal M. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935; 29:181.
Association between bilateral polycystic ovaries and signs of amenorrhea, oligomenorrhea, hirsutism, and obesity.
Most patients resumed menses and achieved pregnancy after ovarian wedge resection (at least one half of each ovary).

5. The polycystic ovary
The characteristic polycystic ovary emerges when a state of anovulation persists for any length of time.
Because there are many causes of anovulation there are many causes of polycystic ovaries.

6. Ovarian hystologic characteristics
The surface area is doubled
average volume increases 2.8 times.
The number of growing and atretic follicles doubled.
Each ovary may contain cystic follicles(2-10mm)
The thickness of tunica is increased by 50%.
A 5-fold increase in stroma are noted.

8. A: Polycystic ovaries, showing increased size and a smooth white surface reflecting thickening of the capsule. B: Section through polycystic ovary, showing multiple cysts with diameter < 10 mm arranged around the periphery of the ovary. The stroma is increased, and the ovary enlarged.
©The Medical Journal of Australia ISSN: X

9. Diagnosis of PCOS

10. Diagnosis of PCOS

11. Ultrasonography Finding
Enlarged ovaries and necklace –like pattern
Large number (>10) of tiny follicles (cysts) just under the surface of the ovaries
The center of the ovaries is echogenic (highly reflective on ultrasound) and with very few follicles seen.
Women with ultrasound findings are said to have polycystic appearing ovaries (PAO).

12. * Sonography of polycystic ovary.

13. Ultrasonography as a diagnostic tool for PCOS is unnecessary.
From %8 - %25 of normal women will demonstrate ultrasonographic picture.
This woman are endocrinology normal and polyscystic ovaries observed with ulteasonography are associated with impaired fertility only when accompanied by symptoms of menstural irregularities and hyperandrogenism.

14. The cause of PCOS is most likely multiple factors, and genetic abnormalities may be involved
PCOS as a heterogeneous disorder of unknown cause with various clinical features that can be divided into 3 categories:
clinical,
endocrine, and
metabolic.

15. What signs and symptoms can be found in women with polycystic ovary syndrome (PCOS)? Ovulation problems Anovulation
Oligo-ovulation
Infrequent or irregular ovulation
Irregular menstrual cycles (results from not ovulating regularly) Amenorrhea
Oligomenorrhea %-50%
Infrequent periods
Hypermenorrhea
Metorrhagia %
Menometorrhagia

16. Elevated androgen levels can result in the development of some signs and symptoms in women
Hirsutism:
Unwanted hair growth. Usually on the lip- cheeks- chin neck-in between the breasts(70%).
Acne
Alopecia

17. Clinical Features of PCOS
Ovulatory dysfunction
Amenorrhea
Oligomenorrhea
Irregular uterine bleeding
Infertility
Androgen excess
Hirsutism
Seborrhea
Acne
Alopecia
Virilization
Insulin resistance
Acanthosis nigricans

20. Young woman with PCOS showing facial hirsutism (A) and axillary acanthosis nigricans (B). The latter is associated with severe insulin resistance and hyperinsulinaemia and is an occasional finding in PCOS (photographs courtesy Dr John Casey, St Vincent’s Clinic, Sydney, NSW).
©The Medical Journal of Australia ISSN: X

21. Endocrine abnormality
Increased frequency of GNRH pulsatile secretion
The higher mean concentrations of LH but low or low-normal levels of FSH.( LH/FSH )
The average daily productin of Estrogen and Androgens is increased and dependent on LH stimulation
50% reduction in circulating levels of SHBG

22. The higher concentration of:
Testostrone
Androstendion
DHEA- DHEAS
17OHP
EStrone.

23. The circulating estrone levels are due to peripheral conversion of the increased amounts of androstendion to estrone.

24. Etiology of increasing LH/FSH
Increased frequency of GNRH pulsatile secretion.
Increase in LH pulse frequency and pituitary response to GNRH are characteristic of the anovulatory state

25. Because the FSH levels are not totally depressed ,new follicular growth is continuosly stimulated but not to the point of full maturation and ovulation.
FSH new follicular
growth
and atresy

26. Cholestrol testostrone
Theca cell LH
Granulosa cell
FSH
Cholestrol testostrone
Androstenedion
Estrone Estradiol

28. Hyperandrogenism effect in ovary
Androgens conver to 5a-reduced metabolites that inhibit aromatase activity
Preventing normal cycle and ovulation
Preventing follicular development and inducing premature atresia of folliculi

29. Hyperandrogenism effect in ovary
Atresia
degenerating granulosa
leaving the theca cells to the stromal
Androgens

30. Increased free estradiol and estrone
FSH LH/FSH

31. Insulin
has an stimulatory effect on ovarian androgen production

32. Genetic consideration
X- linked dominant transmission
Autosomal- dominant
The stimulatory effect of insulin on ovarian androgen production is influenced by genetic predisposition

33. Insulin Resistance and Hyperandrogenism
The association between increased insulin resistance and PCOS is now well – recognized.

34. Questions
1- Which coms first , the hyperinsulinemia or the hyperandrogenism?
2- How does hyperinsulinemia produce hyperandrogenism?
3- Are all women with PCOS have hyperinsulinemia?

35. 1_ Hyperinsulinemia is the primary factor
GNRH agonist and correction hyper androgenism
Administration of insulin and glucose
Weight loss
Invitro , insulin stimulates theca cell androgen production

36. 2_ How does hyperinsulinemia produce hyperandrogenism?
Insulin binds to IGF-1 receptors
increase androgen production
in theca cells

40. Are all women with PCOS have hyperinsulinemia?
Not every women with PCOS has hyperinsulinemia not even every overweight.
Hyperinsulinemia can be an underlying disorder.

41. 4 - why not all women who are insulin resistant hyperandrogenic?
The answer to this question is not known.
But a logical speculation is that an ovarian genetic susceptibility is required or existence of long-term anovulation must be present and even precede hyperinsulinemia.

42. Metabolic syndrome
multiple studies indicate that women with PCOS are at increased risk for the development of glucose intolerance or frank type 2 diabetes mellitus, hypertension, dyslipidemia, and atherosclerosis.

43. Clinical consequences
Infertility
AUB
Hirsutism-acne and alopecia
Endometrial cancer and perhaps breast cancer.
Cardiovascular disease
T2DM in patients with insulin resistant
HTN
HLP

45. Laboratory Tests for the differential Diagnosis of Androgen Excess
Initial testing
Total testosterone
Prolactin
TSH
Further testing based on clinical presentations
17-OH-progesterone (8:00 AM) – CAH : >2 ng/mL
17-OH-progesterone 60 min after iv. ACTH – CAH : > 10 ng/mL
Cortisol (8:00 AM) after 1 mg dexamethasone at midnight – Cushing’s : > 5 ug/dL or > 2 ug/dL
DHEAS – Adrenlal tumors : > 8 ug/mL (but also in 50% of PCOS)
Androstenedione
Imaging of ovaries (transvaginal ultrasonography)
Imaging of adrenals (ABD echo, adrenal CT scan, adrenal MRI)
Nuclear imaging after iv. radiolabeled cholesterol

46. Treatment
Hyperandrogenism
Endometrium protect
Hyperinsulinemia
prevent of CVD
Induced ovulation

47. Endometrium protection
Endometrial Biopsy
1- Duratin of exposure to unopposed estrogen is critical.
2- Endometrial Thickness is greater than 12mm

48. Medroxy progestron: 14 days every month OCP 1- Androgen suppression
2- Improvement in lipid profile
3 - protectin of endometrium

49. Insulin Resistance The best therapy is weight loss>5% BMI<27
Lifestyle improvement with proper diet and exercise
Druge agent : Metformin and Glitazones

50. Management of PCOS Lifestyle changes: diet, exercise, weight reduction
Insulin sensitizers
Metformin
Thiazolidinediones (TZD)
Oral contraceptives

51. Management of PCOS Metformin Reduce hyperinsulinemia
Reduce basal and stimulated LH levels
Reduce free testosterone concentrations
Increasing menstrual cyclicity
Induce ovulation and pregnancy
GI side effects to cause weight reudction

52. Management of PCOS Metformin
Use at doses of 500–2500 mg daily is controversial. (mostly, 500 mg Tid)
Recent systematic reviews suggest that the drug has efficacy for ovulation induction, either as a sole agent or in combination with clomiphene citrate.

53. Metformin Weight loss Ovulation Diabetes risk reduction
CVD risk reduction
It is important component of health care of women with PCOS.

54. Management for Hirsutism
Oral contraceptive pill (ex, ethinyloestradiol 35 ug + cyproterone acetate 2 mg daily for 21 of 28 days)
Cosmetic measures (ex, laser electrolysis, bleaching, waxing or shaving)
Oral estrogen + cyproterone acetate (estradiol valerate 2 mg daily and cyproterone acetate 50 mg for 14 days a month)
Spironolactone (75–200 mg daily)
Other drugs, such as the anti-androgen flutamide (treatment of prostate cancer) or the antifungal agent ketoconazole. These drugs either reduce androgen production or inhibit androgen-binding to the receptor. They are not in general use for this purpose.
Response times for drugs can be up to 3 months

55. Cyproterone Acetate
17-OH-progesterone acetate derivatives with strong progestagenic properties.
Acts as an anti-androgen by competing with DHT and testosterone for binding to the androgen receptor.
Cyproterone acetate + ethinyl estradiol in combination can inhibit 5α-reductase activity in skin.
Mostly administered in doses of 50~100 mg/day from day 5 through day 15 of the treatment cycle. Combined with ethinyl estradiol (50 ug/day) between day 5~day 26 for menstrual control.

56. Management for Infertility
Lifestyle changes and weight reduction
Metformin
Clomiphene citrate
An oral estrogen antagonist that raises circulating concentrations of FSH and induces follicular growth in most women with PCOS and anovulation.
The initial regimen is 25–50 mg per day for 5 days. Therapy can be monitored by estrogen levels, follicular ultrasound examination and luteal progesterone level (> 20 nmol/L).
Failure of response is associated with high body mass index and high androgen levels. Doses up to 200 mg per day can be used before failure of response is established.
In the rare situation in which side effects limit treatment, tamoxifen can be used. Both treatments increase the risk of multiple pregnancy.

57. Management for Infertility
Gonadotropin therapy
Need skill and experience to avoid multiple pregnancies and ovarian hyperstimulation syndrome (esp. on conventional-dose gonadotropin therapy – 150 IU FSH, +75 IU every 3~7 days).
Low-dose recombinant FSH (75 IU for 14 days) administered subcutaneously.
Monitoring of ovarian response involves ultrasound examination, often with estradiol measurement. Human chorionic gonadotrophin (HCG) is given when one follicle reaches 16–20 mm in size. Any more than two follicles of an appropriate size gives the risk of multiple pregnancies. Multiple gonadotropin cycles may be required to achieve pregnancy, but this approach is preferable before more invasive procedures, such as in-vitro fertilisation

58. Management for Infertility
In-vitro fertilisation (IVF)
Provided there is no problem other than anovulation, this has little place in the management of infertility resulting from PCOS.
Ovulation induction by a skilled reproductive endocrinologist is preferable to in-vitro fertilisation because of the risks of hyperstimulation and multiple pregnancy with the latter procedure.

59. THE Best Wishes For You