In The Name Of God

PCOS

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

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).

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.

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 20- 100 cystic follicles(2-10mm)The thickness of tunica is increased by 50%.A 5-fold increase in stroma are noted.

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 2004 www.mja.com.au ISSN: 0025-729X

Diagnosis of PCOS

Diagnosis of PCOS

Ultrasonography FindingEnlarged 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).

* Sonography of polycystic ovary.

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.

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.

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 20%-50% Infrequent periods Hypermenorrhea Metorrhagia 30% Menometorrhagia

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

Clinical Features of PCOS

Ovulatory dysfunction• Amenorrhea• Oligomenorrhea• Irregular uterine bleeding• Infertility

Androgen excess• Hirsutism• Seborrhea• Acne• Alopecia• Virilization

Insulin resistance• Acanthosis nigricans

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 2004 www.mja.com.au ISSN: 0025-729X

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

The higher concentration of:

Testostrone Androstendion DHEA- DHEAS 17OHP EStrone.

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

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

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

Theca cell LH

Granulosa cell

FSH

Cholestrol testostrone

Androstenedion

Estrone Estradiol

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

Hyperandrogenism effect in ovary

Atresia

degenerating granulosa leaving the theca cells to the stromal

Androgens

Increased free estradiol and estrone

FSH LH/FSH

Insulin has an stimulatory effect on ovarian androgen production

Genetic consideration

X- linked dominant transmission

Autosomal- dominant

The stimulatory effect of insulin on ovarian androgen production is influenced by genetic predisposition

Insulin Resistance and Hyperandrogenism

The association between increased insulin resistance and PCOS is now well – recognized.

Questions

1- Which coms first , the hyperinsulinemia or the hyperandrogenism?

2- How does hyperinsulinemia produce hyperandrogenism?

3- Are all women with PCOS have hyperinsulinemia?

1_ Hyperinsulinemia is the primary factor

GNRH agonist and correction hyper androgenism

Administration of insulin and glucoseWeight loss Invitro , insulin stimulates theca cell

androgen production

2_ How does hyperinsulinemia produce hyperandrogenism?

Insulin binds to IGF-1 receptors

increase androgen production in theca cells

Are all women with PCOS have hyperinsulinemia?

Not every women with PCOS has hyperinsulinemia not even every overweight.

Hyperinsulinemia can be an underlying disorder.

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.

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.

Clinical consequences Infertility AUB Hirsutism-acne and alopecia Endometrial cancer and perhaps

breast cancer. Cardiovascular disease T2DM in patients with insulin

resistant HTN HLP

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

Treatment

Hyperandrogenism Endometrium protect Hyperinsulinemia prevent of CVD Induced ovulation

Endometrium protection

Endometrial Biopsy 1- Duratin of exposure to unopposed

estrogen is critical.2- Endometrial Thickness is greater

than 12mm

Medroxy progestron: 14 days every month

OCP

1- Androgen suppression 2- Improvement in lipid profile 3 - protectin of endometrium

Insulin Resistance

The best therapy is weight loss>5%BMI<27Lifestyle improvement with proper diet and exerciseDruge agent : Metformin and Glitazones

Management of PCOS

Lifestyle changes: diet, exercise, weight reduction

Insulin sensitizers• Metformin• Thiazolidinediones (TZD)

Oral contraceptives

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

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.

Metformin

Weight loss Ovulation Diabetes risk reduction CVD risk reduction

It is important component of health care of women with PCOS.

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

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.

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.

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

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.

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