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.
THE Best
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