Prof. Mahmoud Zakherah Prof of Obstetrics and Gynecology,

Women’s Health Hospital Assiut mszakhera@gmail.com

2017

Definitions Infertility

Subfertility

Sterility

Physiological backgrounds Hypothalamus

Gonadotrophin-releasing hormone (GnRH)

pulsatile secretionPituitary

FSHLHProlactin

Ovary EstradiolProgesteroneAMH

Physiological backgrounds Menstrual cycle Ovarian cycle

Ovarian cycle

RecruitmentSelectionDominanceOvulation

Estradiol surge 36h LH surge- 36h -+ve feedback mechanism Ovulation------fertilization—implantation

Ovarian cycle

Unripe follicle

Ripening follicle

Ovulation Corpus luteum

Regression of Corpus luteum

Etiology of infertility

Ovulatory disordersOvulatory disorders are a common

cause of infertility 20% , which in most cases is treatable with ovulation induction agents.

The goal of therapy in these women is monofollicular development and subsequent ovulation.

Ovulatory disordersThe method of ovulation

induction selected by the clinician should be based upon the underlying cause of anovulation and the efficacy, costs, risks, and potential complications associated with each method as they apply to the individual woman.

Diagnosis of Ovarian factor

Diagnosis of Ovarian factor

Investigations Ovulation monitoring: (transvaginal

sonography (follicle 18mm) U/S: folliculometry

Midluteal progesterone: (day 21) >3 ng/ml, >10 ng/ml

Premenstrual biopsy : (PEB): Secretory changes (not done)---???????

Endometrial scratching

Ovulation monitoring Folliculometry Trilaminar endometrium

Anovulation

WHO Classification of Anovulation WHO type 1 (hypogonadotropic hypogonadism),

can be caused by any lesion affecting the pituitary or hypothalamus and affecting gonadotropin production

WHO type 2 (normogonadotropic hypogonadism) is by far the commonest cause of anovulation and is most commonly caused by polycystic ovarian syndrome.

WHO type 3 (hypergonadotropic hypogonadism) is usually an indication of ovarian failure.

WHO Group II (hypothalamic pituitary dysfunction (70 to 85 %(

Hypothalamic pituitary dysfunctionEugonadotrophic=NormogonadotrophicThis includes a heterogeneous group of patients who

can present either with regular cycle oligomenorrhoea, or even amenorrhoea.

The midluteal serum progesterone is low, FSH levels are in the normal range and prolactin is normal.

Most of these patients are likely to have PCOS.

WHO Group II (hypothalamic pituitary dysfunction (70 to 85 %)

Treatment I-Non pharmacologic Weight loss and exercise life style modification

II–Pharmacologic Antiestrogens as CC tamoxifen or combinationHuman gonadotrophinsInsulin sensitizersDopamine agonistsAromatase inhibitorsIII - Surgical induction of ovulation

(LOD)

Surgical Induction of

Ovulation

P C O SPCOS is a heterogenous disorder.

Clinical verities.Wedge resection 1935.CC 1960.LOD Gjönnaess 1984

Women with polycystic ovary syndrome who have not responded to clomifene citrate should be offered laparoscopic ovarian drilling because it is as effective as gonadotrophin treatment and is not associated with an increased risk of multiple pregnancy level (A) evidence

Normal ovary A N

Normal Ovary measures an average of 6.5ml (5.4-7.6ml) in premenopausal women

Laparoscopic Ovarian Drilling (LOD(

Mechanism of action of LODThe mechanisms of action are not understood Placebo effect(Aono et al, 1976)Destruction of androgen producing ovarian stromaCorrecting abnormal ovarian pituitary feedback (Balen and

Jacobs, 1994)VEGF and IGF-1, which are typically increased in patients

with PCOS(Amin et al,2003)Reduction of ovarian inhibin with a resultant rise in

FSH ????(Amer et al,2007 found no change)

Mechanism of action of LOD

Puncturing of follicles androgens . Crowding of follicles.

LH FSH

Not HOW but WHY

Indications of LODCC resistant PCOSPersistent high LHIntolerable side effects of drugs as

CC and HMG.Other indications of laparoscopy.No available or feasible

monitoring .

Indications of LODDecrease OHSS in ART cycles. (Amer et al,2007Recurrent miscarriage ? High LH.Prevention of long term

morbidity (metabolic and cardiovascular risks found no benefit ).

Advantages of LODSingle action.No intense monitoring.Less expensive than gonadotropinsMonofollicular ovulationNo risk of multiple pregnancy.Less OHSSLess RPL due to effect on LH Long lasting effect 12-18 mo. .

Evolution of Surgical management of PCOS

Initially , laparoscopic wedge resection Biopsy (celioscopic ovarian resection) multiple

small ("punch") biopsies of the ovarian surface (Sumioki, 1988).

] Laparoscopic ovarian diathermy (Gjonnaess ,1984). Needle point electrode (drilling), (4-10 points (92%-69%).

Laser vaporization or photo-coagulation (Daniell, 1989)

Evolution of Surgical management of PCOS

Transvaginal ultrasound follicular aspiration (Maio et al , 1991).Cryocautery ( Ali ,1992 ).Bipolar diathermy of PCO (Kovacs, 1993).Endo coagulation (Amin,1994).

Evolution of Surgical management of PCOSUnilateral ovarian drilling (Balen and Jacobs,1994). Single Puncture Electrocoagulation of Ovarian Stroma "SPECOS“ Shawki,1996Transvaginal ultrasound-guided electrocautery (Syritsa,1998)Removing one ovary (Kaaijk, 1999).Transvaginal hydrolaparoscopy (Gordts et al,2009,fertil steril).Single port laparoscopic surgery LOD (2010)

UNILATERAL VERSUS BILATERAL LAPAROSCOPIC OVARIAN DRILLING (LOD) IN WOMEN

WITH POLYCYSTIC OVARIAN SYNDROME (PCOS): A RANDOMIZED CLINICAL TRIAL Alaaeldin A. Youssef (MD), Mahmoud S. Zakherah (MD), Esam A. Khalifa (MD), Ahmed F Amin (MD)and Mohamed MF Fathalla (MD)(2003) Conclusions : Unilateral LOD is as effective as bilateral LOD as regards resumption of regular men-strual cycles, ovulation and pregnancy rate, and en-docrinological changes. Unilateral LOD is superior to bilateral LOD, it has the advantages of less ther-mal damage to the ovaries, shorter operative time and less CO2 consumption and fewer incidences of postoperative adnexal adhesions.

Methodology of Ovarian Drilling Preoperative requirements Documented PCOS (clinical, hormonal and

sonographic). Rotterdam2004-AES 2009Clomiphene resistance 150mg 3cyclesNormal prolactin or treated.Inability or unwilling to undergo gonadotropin

therapyNormal endometrial cavity with patent tubes(HSG).Normal semen analysis

Documented PCOS

TVS

LAPAROSCOPY

Documented PCOS

Methodology of Ovarian DrillingOperative requirementsExtended lithotomy positionGeneral endotracheal anesthesia - Spinal ?? 10mm or 5mm telescope Angle ZeroVideo assisted triple puncture laparoscopy High flow CO2 insufflator Atraumatic grasper .Monopolar needle

Methodology of Ovarian DrillingInstillation of Ringer’s lactate (300

ml) into the pouch of Douglas to enhance ovarian cooling after drilling {hydrocortisone+Heparin}

Grasping of the ovarian ligament or flipping over the ovary,

The ovary is lifted then rotated and then puncture.

Methodology of Ovarian DrillingUnipolar current is advised in a cutting

mode to minimize thermal damage; the power is activated just before touching the ovary (Corson needle) (Bipolar-LASER may be used ).

Antimesenteric border perpendicular The number of cauterization points

depends on the ovarian volume (4-10 punctures).

Methodology of Ovarian Drilling Avoid cauterization at MesovariumHilumCorpus luteumOvarian ligamentInfudibulopelvic ligament

How many punctures?

How many punctures

How many punctures? Too little is insufficient

Too much is harmful

The solution is : Adjust

How many punctures? In earlier studies (Gjonnaess,1989) there was an assumption that the greater the amount of energy, the more effective the procedure.

How many punctures?

Later on, lower thermal doses through use of a fixed number of puncture points regardless of ovary size (Felemban et al,2000) or unilateral ovary cauterization had been reported, aiming to decrease the potential risks of ovarian failure and adnexal adhesions (Balen and Jacob,1994).

How many punctures? Rule of Four 40 W-4 seconds-4 puncture points(rule 0f 4).After diathermy, each ovary should be lowered into the pool of saline.No coagulation should be done within 1 cm from the helium.At the end of the procedure both ovaries should be irrigated with Ringer's lactate. It was concluded that “the solution to pollution is dilution“.

How many punctures? Zakherah et al 2010, concluded that adjusted diathermy dose based on ovarian volume for laparoscopic ovarian drilling of polycystic ovary syndrome has a better reproductive outcome compared with fixed thermal dosage.

Adjusted LOD New terminology Means tailoring the number of punctures

according to Ovarian Volume (Zakherah et al ,2011)

Adjusted LODBecause we were planning to use the least

effective dose, our suggested dose was 625 J/10.8 cm3= 60 J/cm3 of ovarian tissue. The required number of punctures then was calculated by dividing total individual ovarian dose with dose delivered in each puncture point. ( e.g. 12 cm3 x60=720 j ÷150=4.8 punctures)

Adjusted LOD

LOD using a thermal dose of 60 J/cm3 (adjusted LOD) has a better reproductive outcome compared with fixed thermal dosage of 600 J per ovary in treatment of patients with PCOS with CC resistance.

Adjusted ovarian drilling based on ovarian volume has no detrimental effect on the ovarian reserve

.

Predictors of the outcome Clinical predictorsMarked obesity(BMI≥35)History of infertility >3 years .Biochemical predictors High LH levels≥10IU)Marked hyperandrogenemia.Insulin resistance (Amer et al,2004)

2014

Outcomes of Ovarian Drilling

Clinical Outcome of Ovarian Drilling Restoration of regular menstruation in approximately 80%.The mean ovulation rate was 70% and the cumulative

pregnancy and live birth rate was 76% and 64% , respectively (Bayram et al,2004)

Miscarriage rate is similar to general population .Reproductive performance seems to last for may years in

about one third of cases (Amer et al,2002).

Outcome of Ovarian Drilling Hormonal Changes After Ovarian Drilling Decline in the LH levels Decrease in androgens (testosterone and

androstenedione) (Armar etal,1990)Increase in serum prolactin Rise in FSH levels ?(Api ,2008=no change )Gjonnaess (1998) concluded that ovarian electrocautery

for PCOS normalizes ovarian function including androgen production, and these results seem to be stable for 18-20 years

Unilateral versus Bilateral Unilateral as effective as bilateral

Contralateral ovary may ovulate first (Al-Mizyen and Grudzinskas 2007)

Complications of ovarian drilling

A part from the need of surgery under general anesthesia and the risk of any surgical procedure 1- Pelvic adhesions Adhesion formation rates following laparoscopic ovarian drilling ranged from zero (Daniell and Miller, 1988) to 100% (Greenblatt and Casper, 1987).Lt more prone to adhesionsThe mean adhesion score of the patient treated with CO2 laser was significantly higher than that treated with electrocautery (Cohen, 1995).

Complications of ovarian drilling Factors influencing adhesion formation Thermal dosage (So the reduction in damage was produced by

unilateral ovarian drilling (Roy et al ,2009)may reduce the postoperative adhesion formation).

Armor recommend 4p-40ws-4 sec stromal not surface –perpendicular Pelvic lavage and induction of artificial ascites“the solution to pollution is dilution“200 Hartmann’s-cooling

Complications of ovarian drilling 2- Ovarian atrophy and premature ovarian failure Ovarian atrophy has been reported by Dabirashrafi (1989) as a complication of excessive drilling of polycystic ovaries. It is therefore advised that no coagulation should be done within 1 cm of the ovarian helium, the number of cauterization points should be individualized according to the ovarian size and the wattage chosen should depend on the thickness of the ovarian capsule .

Is ovarian reserve diminished after laparoscopic ovarian drilling?

The PCOS women both with and without LOD had significantly greater ovarian reserve than the age-matched controls having normal ovulatory menstruation (Weerakiet et al ,2007). LOD, if applied properly, normalizes the exaggerated ovarian morphologic and endocrinologic properties. (normalization of ovarian function rather than a reduction of ovarian reserve )(Api,2009)

.

The impact of laparoscopic ovarian drilling on AMH & ovarian reserve: a meta-analysis April 2017Saad A Amer1, Tarek T El Shamy2, Cathryn James, Ali

H Yosef , Ahmed A. Mohamed,

LOD significantly lowers circulating AMH, but this may not necessarily reflect a real damage to ovarian reserve. Given its proven efficacy and its long-term benefits, LOD should remain as an option in the management of anovulatory PCOS patients.

How to avoid DOR AdjustCutting modeShort timeLow wattageLavageUnilateralNever drill

Complications of ovarian drilling

3- Epithelial ovarian tumors There is a theoretical concern that ovarian drilling may

increase the incidence of epithelial ovarian tumors There is no long-term follow-up to evaluate this

association

LOD Vs Gonadotropin therapy

NO difference in the live birth rate and miscarriage rate in women with Clomiphene-resistant PCOS undergoing LOD compared to gonadotrophin treatment. The reduction in multiple pregnancy rates in women undergoing LOD makes this option attractive. However, there are ongoing concerns about long-term effects of LOD on ovarian function. Farquhar et al,2007. Cochrane Database Syst Rev. 2007).

Failed LOD 20-30% of anovulatory women with PCOS

failed to respond to LOD (Farquhar,2004).Insufficient thermal dosageInherent resistance ovary to the effects of

drilling.post-operative adhesionHyper prolactaenaemia observed in some

patients after LOD

Adjuvants after ovarian drilling

CC or low dose gonadotropins NAC is a novel adjuvant therapy after unilateral LOD which might help improve overall reproductive outcome (a pilot study ) (Nasr A,2010).Metformin increases the ovulation and pregnancy rates in infertile women, following LOD(Kocak and Ustün ,2006).Weight reduction.IVF.Repeat LOD ,we will add more complications

Repeated LOD in polycystic ovary syndrome

Repeat LOD is highly effective in women who previously responded to the first procedure (Amer ,et al ,2003).

DO NOT Repeat You will repeat failureAfter 1 y follow up IVFAntagonist Vs Long protocols

Current status in LODLOD may be preferred as 2nd line therapy (Amer,2008)

LOD and gonadotropins have been shown to be equally effective in ovulation and pregnancy rates(Farquhar et al,2005). (Moderately quality evidence)

The Society of Obstetricians and Gynecologists of Canada 2010 1-Weight loss, exercise, and lifestyle modifications

have been proven effective in restoring ovulatory cycles and achieving pregnancy in overweight women with PCOS and should be the first-line option for these women. (II-3A).

2. Clomiphene citrate has been proven effective in ovulation induction for women with PCOS and should be considered the first-line therapy.. (I-A)

The Society of Obstetricians and Gynecologists of Canada 20103-Metformin may be added to clomiphene citrate in women

with clomiphene resistance who are older and who have visceral obesity (I-A).. Metformin combined with clomiphene citrate may increase ovulation rates and pregnancy rates but does not significantly improve the live birth rate over that of clomiphene citrate alone (I-A) .

4. Gonadotropins should be considered second-line therapy for fertility in anovulatory women with PCOS. The treatment requires ultrasound and laboratory monitoring. High costs and the risk of multiple pregnancy and ovarian hyperstimulation syndrome are drawbacks of the treatment (II-2A).

The Society of Obstetricians and Gynecologists of Canada 20105. Laparoscopic ovarian drilling may be considered

in women with Clomiphene-resistant PCOS, particularly when there are other indications for laparoscopy. (I-A)

Surgical risks need to be considered in these patients. (III-A).

6. In vitro fertilization should be reserved for women with PCOS who fail gonadotropin therapy or who have other indications for IVF treatment (II-2A).

is it time to relinquish the procedure?

1. LOD is a safe and cost effective procedure.2. A single treatment results in uni- follicular

ovulation.3. No need of continuous monitoring as seen

with hormonal treatment. 4. No fear of multiple births and ovarian

hyper stimulation. 5. LOD increase the sensitivity to

gonadotrophins and it is as effective as gonadtrophins in PCOS

2016

Conclusion

Surgical treatment of PCOS not recommended to be the first line of treatment but are advisable for clomiphene resistant cases, as they are not free of adverse effects.

Never DrillOvarian volume less than 10 cm3.

FSH more than 9 IU/LPrevious ovarian drilling .except

AMH less than 5 ng/mlOnly used as a 3rd line therapy

Never Drill