Surgical Treatment of Surgical Treatment of Endometriosis: When is it Endometriosis: When is it

worth the risk?worth the risk?

Tommaso Falcone MDTommaso Falcone MD

Cleveland Clinic FoundationCleveland Clinic Foundation

Attestation Disclosure to AudienceAttestation Disclosure to AudienceDepartment of Obstetrics and Gynecology Grand RoundsDepartment of Obstetrics and Gynecology Grand Rounds

February 5,2009February 5,2009Tommaso Falcone, MDTommaso Falcone, MD

Surgical Treatment of EndometriosisSurgical Treatment of Endometriosis

• In accordance with the standards of the Accreditation Council for In accordance with the standards of the Accreditation Council for Continuing Medical Education (ACCME), all speakers are asked to Continuing Medical Education (ACCME), all speakers are asked to disclose any real or apparent conflicts of interest or discussion of off-disclose any real or apparent conflicts of interest or discussion of off-label use of product(s) or device(s). The ACCME also requires label use of product(s) or device(s). The ACCME also requires disclosure of any commercial support.disclosure of any commercial support.

• Today’s speaker disclosed: Consultant with Gynesonics.Today’s speaker disclosed: Consultant with Gynesonics.

• Today’s speaker has one slide for off-label or investigational use(s) of Today’s speaker has one slide for off-label or investigational use(s) of a product or device: an off label use of the Mirena IUD/letrzole. a product or device: an off label use of the Mirena IUD/letrzole.

• There was no commercial support for this programThere was no commercial support for this program

Learning ObjectivesLearning Objectives

This session will:This session will:• Enable a physician to assess the Enable a physician to assess the

outcome (pain relief or pregnancy) of outcome (pain relief or pregnancy) of surgical treatment for endometriosis.surgical treatment for endometriosis.

• Enable a physician to evaluate the Enable a physician to evaluate the value of postoperative medical therapyvalue of postoperative medical therapy

• Familiarize the physician with the Familiarize the physician with the different surgical techniques used to different surgical techniques used to treat endometriosistreat endometriosis

Symptoms & Signs of Symptoms & Signs of advanced endometriosisadvanced endometriosis

• Chapron et al 2005Chapron et al 2005• ““Presurgical diagnosis of posterior Presurgical diagnosis of posterior

deep infiltrating endometriosis based deep infiltrating endometriosis based on a standardized questionnaire”on a standardized questionnaire”– Painful defecation during mensesPainful defecation during menses– Severe dyspareuniaSevere dyspareunia– Previous surgery for endometriosisPrevious surgery for endometriosis

Diagnostic work-upDiagnostic work-up

• History ( dysmenorrhea, dyspareunia & History ( dysmenorrhea, dyspareunia & noncyclic pelvic pain)noncyclic pelvic pain)

• Physical exam: adnexal mass, non mobile Physical exam: adnexal mass, non mobile uterus or cul-de-sac nodularity.uterus or cul-de-sac nodularity.

• CA-125CA-125– Meta-analysisMeta-analysis– Sensitivity of 28 % showed a specificity of 90%Sensitivity of 28 % showed a specificity of 90%– Sensitivity of 50% showed a specificity of 72%Sensitivity of 50% showed a specificity of 72%

Role of ImagingRole of Imaging

• Transvaginal ultrasound has a high Transvaginal ultrasound has a high sensitivity & specificity in the diagnosis sensitivity & specificity in the diagnosis of ovarian endometriotic cystof ovarian endometriotic cyst

• MR & CT have no added advantage MR & CT have no added advantage • Trans-rectal ultrasound may have some Trans-rectal ultrasound may have some

value for recto-vaginal endometriosis value for recto-vaginal endometriosis (Fedele et al Obstet & Gynecol 1998) (Fedele et al Obstet & Gynecol 1998)

• Imaging has a low sensitivity & Imaging has a low sensitivity & specificity for non-ovarian endometriosisspecificity for non-ovarian endometriosis

Imaging for advanced Imaging for advanced endometriosisendometriosis

• Ghezzi et al 2005Ghezzi et al 2005

• Ultrasound Ultrasound – Detection of “kissing ovaries” at Detection of “kissing ovaries” at

ultrasound is strongly associated with ultrasound is strongly associated with severe endometriosis severe endometriosis

Histologic diagnosisHistologic diagnosis

• Mettler et al JSLS 2003Mettler et al JSLS 2003• Histologic confirmation in visually Histologic confirmation in visually

identified endometriosis: 54%identified endometriosis: 54%• ““red” lesions: 100%red” lesions: 100%• ““black” lesions: 92%black” lesions: 92%• ““white” lesions:31%white” lesions:31%• Sites: least probable on the ovary, Sites: least probable on the ovary,

bowel serosa, bladder peritoneumbowel serosa, bladder peritoneum

Treatment: Infertile PatientTreatment: Infertile Patient

Treatment effectTreatment effect

• Treatment effect large enough to be Treatment effect large enough to be clinically relevant?clinically relevant?

• Number needed to treat (NNT): Number needed to treat (NNT): number of subjects that must be number of subjects that must be treated to achieve one more outcome treated to achieve one more outcome with intervention than controlwith intervention than control

• NNT=1/Risk differenceNNT=1/Risk difference• Risk difference: Event rate treated Risk difference: Event rate treated

group- Event rate controlgroup- Event rate control

Treatment effectTreatment effect

• Canadian study Canadian study – N=172 treated & N=169 untreatedN=172 treated & N=169 untreated– PR% 29% treated & 17% untreatedPR% 29% treated & 17% untreated– NNT= 1/.12=8.3NNT= 1/.12=8.3– NNT=9, 95 % CI, 5,33NNT=9, 95 % CI, 5,33

• Italian studyItalian study– N=54 treated & N=47 no treatmentN=54 treated & N=47 no treatment– PR% 22% & 28%PR% 22% & 28%

Treatment EffectTreatment Effect

• Canadian study PR for pregnancies Canadian study PR for pregnancies more than 20 weeks of gestation, more than 20 weeks of gestation, Italian study reported any Italian study reported any pregnanciespregnancies– Combine the studies for pregnancies Combine the studies for pregnancies

over 20 weeks: 27% (treated) & 18% over 20 weeks: 27% (treated) & 18% ( non treated): NNT=12 ( 95% CI 6,112)( non treated): NNT=12 ( 95% CI 6,112)

– 20% prevalence of endometriosis20% prevalence of endometriosis– 60 diagnostic laparoscopies to get an 60 diagnostic laparoscopies to get an

extra pregnancyextra pregnancy

Moderate-Severe Moderate-Severe Endometriosis: Result of Endometriosis: Result of

surgerysurgery• Candiani et al 1991Candiani et al 1991

– 206 patients/15 studies: MFR:3%; 206 patients/15 studies: MFR:3%; CPR:47%CPR:47%

• Luciano et al 1992: Luciano et al 1992: – MFR 6.7%; CPR 70%MFR 6.7%; CPR 70%

• Busacca et al J Am Ass Gyn L 1999Busacca et al J Am Ass Gyn L 1999– Prospective study; MFR: 2.4%; CPR 24 Prospective study; MFR: 2.4%; CPR 24

months 57%months 57%

Stage III&IV EndometriosisStage III&IV EndometriosisPagidas et alPagidas et al

Fertility & Sterility 1996Fertility & Sterility 1996

Stage III&IV endometriosisStage III&IV endometriosis

• After initial unsuccessful operative After initial unsuccessful operative procedure to restore fertility , IVF-ET procedure to restore fertility , IVF-ET appears to be a superior alternative appears to be a superior alternative to re-operationto re-operation

Impact of endometriosis on Impact of endometriosis on IVF outcome: Meta-analysisIVF outcome: Meta-analysis

• 22 studies ( 2377 with endometriosis & 22 studies ( 2377 with endometriosis & 4383 without endometriosis); Barnhart et 4383 without endometriosis); Barnhart et al F&S 2002al F&S 2002

• Stage I & II- 21 % per cycle ( control Stage I & II- 21 % per cycle ( control 27.7%)27.7%)– Decrease in implantation & fertilization ratesDecrease in implantation & fertilization rates

• Stage III & IV –13.8 % per cycle ( control Stage III & IV –13.8 % per cycle ( control 27.7%)27.7%)– Decrease in the number of oocytes retrievedDecrease in the number of oocytes retrieved

EndometriomasEndometriomas

• Drainage has a high recurrence rateDrainage has a high recurrence rate

• Need to excise the cystNeed to excise the cyst– Cochrane database 2005 Hart R et alCochrane database 2005 Hart R et al– Excision of cyst associated with a reduced Excision of cyst associated with a reduced

rate of recurrence; reduced symptom rate of recurrence; reduced symptom recurrence and increased spontaneous recurrence and increased spontaneous pregnancy rates compared with ablative pregnancy rates compared with ablative surgerysurgery

EndometriomasEndometriomas

• Jones & Sutton 39.5% PR/12 monthsJones & Sutton 39.5% PR/12 months

• Most studies have shown no impact Most studies have shown no impact on endometriomas on IVF outcomeon endometriomas on IVF outcome

• ESHRE recommendation: remove ESHRE recommendation: remove endometrioma >= 4 cmendometrioma >= 4 cm

Endometrioma Endometrioma surgery:Impact on IVFsurgery:Impact on IVF

• Potential for decreased oocyte recoveryPotential for decreased oocyte recovery• Outcome is dependent on techniqueOutcome is dependent on technique• Minimize damage to the surrounding Minimize damage to the surrounding

tissuetissue

Treatment of Treatment of Infertility:Medical Infertility:Medical

Suppressive therapySuppressive therapy

• Meta-analysisMeta-analysis– No benefit to pregnancy ratesNo benefit to pregnancy rates

Pain ManagementPain Management

Laser Laparoscopy vs Laser Laparoscopy vs Expectant ManagementExpectant Management

Sutton et al Fertil Steril 1994Sutton et al Fertil Steril 1994

• 74 women ( Stage I-III)74 women ( Stage I-III)

• Prospective randomized double blindProspective randomized double blind

• Significant pain relief compared to Significant pain relief compared to expectant management expectant management

• Non response rate was 38 %Non response rate was 38 %

• Results were poorest for Stage IResults were poorest for Stage I

RCT scope excision of endoRCT scope excision of endo

• Abbott et al F&S 2004 Abbott et al F&S 2004 • RCT-placebo trialRCT-placebo trial• Immediate surgery group- 80 % Immediate surgery group- 80 %

response rate at 6 months response rate at 6 months – Far fewer stage I endometriosisFar fewer stage I endometriosis

• Delayed surgery group-30 % Delayed surgery group-30 % response rate at 6 months (placebo response rate at 6 months (placebo effect)effect)

Recurrence RateRecurrence Rate

• Sutton’s trial F&S 1994Sutton’s trial F&S 1994– Follow-up( 1 year) after RCT: Follow-up( 1 year) after RCT: Treated Group that Treated Group that

ImprovedImproved

– 10% recurrence rate10% recurrence rate– Subsequent surgery showed endometriosisSubsequent surgery showed endometriosis

• Abbott et al Human Reproduction 2003Abbott et al Human Reproduction 2003– 135 patients Kaplan –Meier survival curve135 patients Kaplan –Meier survival curve

• Average follow up 3.2 years ( 2-5 years)Average follow up 3.2 years ( 2-5 years)• 36 % probability of further surgery 36 % probability of further surgery • 32 % had no endometriosis32 % had no endometriosis

Years

1 2 3

LaparoscopyHysterectomy (ovaries preserved)Hysterectomy (ovaries removed)

0

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.6

.8

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Reoperation-Free Survival Estimates are Reoperation-Free Survival Estimates are Shown for Groups Defined by Surgery Type Shown for Groups Defined by Surgery Type

and Ovary Preservationand Ovary Preservation

Cleveland Clinic experience. Surgical Treatment of Endometriosis. Obstet Gynecol 2008.

4 5 6 7

Reoperation-Free Survival Stratified by Reoperation-Free Survival Stratified by Potential Factors Affecting OutcomePotential Factors Affecting Outcome

2 Years 5 Years 7 Years HR VersusFactor Frequency (95% CI) (95% CI) (95% CI) (95% CI) Reference Overall

Overall 206 87.4 (82.8-91.9) 70.2 (63.8-76.5) 63.1 (56.2-69.9) NA

Surgery typeLaparoscopic 109 79.8 (72.3-87.4) 54.1 (44.8-63.5) 45.7 (36.3-55.0) 1.0 <.001

Hysterectomy 97 95.9 (91.9-99.8) 89.2 (82.8-95.5) 84.6 (76.8-92.5) 0.20 (0.11-0.36) <.001

Ovaries involvedNo 84 90.5 (84.2-96.7) 71.6 (61.5-81.8) 64.5 (53.2-75.8) 1.0 .64Yes 122 85.2 (79.0-91.5) 68.8 (60.6-77.0) 61.6 (52.9-70.4) 1.12 (0.70-1.79) .64

Colon involvedNo 133 90.2 (85.2-95.3) 72.9 (65.2-80.6) 65.3 (56.8-73.8) 1.0 .42Yes 73 82.2 (73.4) 65.2 (54.2-76.3) 59.1 (47.6-70.6) 1.21 (0.76-1.93) .42

Disease stageI 32 90.6 (80.5-100.0) 70.6 (54.4-86.9) 66.5 (49.2-83.7) 1.0 .74

II 63 88.8 (81.0-96.6) 67.1 (55.2-78.9) 58.5 (45.5-71.5) 0.98 (0.49-1.95) .95III 33 90.9 (81.1-100.0) 80.8 (67.0-94.7) 73.3 (57.2-89.4) 0.66 (0.28-1.56) .34IV 78 83.3 (75.1-91.6) 67.9 (57.5-78.2) 61.1 (50.2-72.0) 0.97 (0.50-1.90) .93

RaceOther 37 81.1 (68.5-93.7) 63.8 (48.0-79.6) 54.3 (37.6-71.1) 1.0 .15White 169 88.8 (84.0-93.5) 71.5 (64.6-78.5) 65.1 (57.6-72.5) 0.67 (0.39-1.15) .15

Surgery age (y)19-29 41 65.9 (51.3-80.4) 39.0 (24.1-54.0) 31.7 (17.5-46.0) 1.0 <.00130-39 93 91.4 (85.7-97.1) 72.0 (62.6-81.3) 62.0 (51.7-72.3) 0.39 (0.24-0.64) <.00140 or older 72 94.4 (89.2-99.7) 85.8 (77.7-94.0) 83.5 (74.4-92.6) 0.15 (0.07-0.29) <.001

Reoperation-Free Survival Stratified by Reoperation-Free Survival Stratified by Potential Factors Affecting OutcomePotential Factors Affecting Outcome

2 Years 5 Years 7 Years HR VersusFactor Frequency (95% CI) (95% CI) (95% CI) (95% CI) Reference Overall

Ages 19-29Overall 41 65.9 (51.3-80.4) 39.0 (24.1-54.0) 31.7 (17.5-46.0) NALaparoscopy 36 63.9 (48.2-79.6) 33.3 (17.9-48.7) 27.8 (13.1-42.4) NA

ovaries preserved

Ages 30-39Overall 93 91.4 (85.7-97.1) 72.0 (62.6-81.3) 62.0 (51.7-72.3) NALaparoscopy 50 88.0 (79.0-97.0) 58.0 (44.3-71.7) 43.8 (30.0-57.6) 1.0 .002ovaries preservedHysterectomy 22 100.0 (100.0-100.0) 95.2 (86.1-100.0) 89.6 (76.0-100.0) 0.13 (0.03-0.54) .005ovaries preserved

Hysterectomy 21 90.5 (77.9-100.0) 85.7 (70.7-100.0) 85.7 (70.7-100.0) 0.23 (0.07-0.74) .014ovaries removed

Ages 40 and olderOverall 70 94.4 (89.2-99.7) 85.8 (77.7-94.0) 83.5 (74.4-92.6) NALaparoscopy 21 85.7 (70.7-100.0) 76.2 (58.0-94.4) 76.2 (58.0-94.4) 1.0 .16

ovaries preservedHysterectomy 21 95.2 (86.1-100.0) 80.4 (63.2-97.7) 64.3 (33.0-95.7) 1.00 (0.29-3.50) .99ovaries preservedHysterectomy 28 100.0 (100.0-100.0) 96.0 (88.3-100.0) 96.0 (88.3-100.0) 0.14 (0.02-1.16) .069

ovaries removed

Hysterectomy in young women Hysterectomy in young women ( less than 30 years of age)( less than 30 years of age)

• Women under 30 ( compared with Women under 30 ( compared with women over 40) women over 40) – 80 % felt that hysterectomy had “cured 80 % felt that hysterectomy had “cured

their pain”their pain”– 18 % had residual symptoms of dyschezia18 % had residual symptoms of dyschezia– 18 % persistent dysuria18 % persistent dysuria– 50 % persistent dyspareunia50 % persistent dyspareunia– 56 % had a “sense of loss”56 % had a “sense of loss”

Postoperative Medical Postoperative Medical TherapyTherapy

• Yap C et al Cochrane Database 2004Yap C et al Cochrane Database 2004– IneffectiveIneffective– Reason? The way it was given?Reason? The way it was given?

• Vercellini et al 2008Vercellini et al 2008– Prevent recurrences of endometriomas while Prevent recurrences of endometriomas while

on the oral contraceptives.on the oral contraceptives.

• Sesti F et al 2007Sesti F et al 2007– Vitamins, minerals, VSL3 lactic ferments, Vitamins, minerals, VSL3 lactic ferments,

omega-3 and omega-6 fatty acidsomega-3 and omega-6 fatty acids

Postoperative Medical Postoperative Medical TreatmentTreatment

• Telimaa et al Gynecol Endocrinol 1987 Telimaa et al Gynecol Endocrinol 1987 Danazol or medroxyprogesterone: no Danazol or medroxyprogesterone: no significant difference in pain scoressignificant difference in pain scores

• Hornstein et al Fertil Steril 1997 Hornstein et al Fertil Steril 1997 nafarelin 200ug BID; no significant nafarelin 200ug BID; no significant

difference in pain scores at 1 year post difference in pain scores at 1 year post surgery; number of patients needing re-surgery; number of patients needing re-treatment within 2 years ( 57% placebo treatment within 2 years ( 57% placebo group & 31% nafarelin group) group & 31% nafarelin group)

Postoperative Medical Postoperative Medical TreatmentTreatment

• Parazzini et al Am J Obstet Gynecol Parazzini et al Am J Obstet Gynecol 19941994

• Stage III & IV endometriosisStage III & IV endometriosis

• Placebo controlled trial, 3 months Placebo controlled trial, 3 months treatment nafarelin, no difference in treatment nafarelin, no difference in pain scores at 12 months follow-up pain scores at 12 months follow-up

Prevention of Recurrent Prevention of Recurrent PainPain

• To be effective you have to use them To be effective you have to use them for long periods of timefor long periods of time

• Why would the effect be protective Why would the effect be protective after discontinuing the drug?after discontinuing the drug?

Long term treatment of Long term treatment of endometriosisendometriosis

• GnRH agonist ( leuprolide)GnRH agonist ( leuprolide)– Treatment extended beyond 6 months if Treatment extended beyond 6 months if

add back therapy usedadd back therapy used– Add back approved by the FDA: Add back approved by the FDA:

norethindrone 5 mg orally dailynorethindrone 5 mg orally daily• Preservation of bone densityPreservation of bone density

– Other add backs:Other add backs:• CEE 0.625mg + MPA 5 mg dailyCEE 0.625mg + MPA 5 mg daily

Other medical treatmentsOther medical treatments

• Depot-Provera SQDepot-Provera SQ• Levonorgestrel-releasing intrauterine Levonorgestrel-releasing intrauterine

system ( Petta et al HR 2005)off labelsystem ( Petta et al HR 2005)off label• Norethindrone 2.5 -5 mg daily without Norethindrone 2.5 -5 mg daily without

agonistagonist• Anastrazole and oral contraceptive Anastrazole and oral contraceptive

agentagent– Off label useOff label use

New drugsNew drugs

• Oral GnRH antagonistOral GnRH antagonist• SPRM ( asoprisnil)-clinical trialsSPRM ( asoprisnil)-clinical trials• COX-2 inhibitorsCOX-2 inhibitors• PPAR ( Peroxisome Proliferator PPAR ( Peroxisome Proliferator

Activated Receptors) agonistsActivated Receptors) agonists• TNF alpha inhibitorsTNF alpha inhibitors

– HR 2008-RCT-no effect-30 % placebo HR 2008-RCT-no effect-30 % placebo effect effect

Endometriosis:Endometriosis:Persistence after TAH+BSOPersistence after TAH+BSO

• Often seen when endometrial implants Often seen when endometrial implants not excisednot excised

• Aromatase expressed in endometriotic Aromatase expressed in endometriotic lesionslesions

• Conversion of adrenal androgens to Conversion of adrenal androgens to estrogen locallyestrogen locally

LUNA procedureLUNA procedure

• Randomized controlled trialsRandomized controlled trials– Sutton et al Gynaecol Endosc 2001Sutton et al Gynaecol Endosc 2001– Vercillini et al Fert & Steril 2003Vercillini et al Fert & Steril 2003

• Proctor et al Cochrane Review, Issue Proctor et al Cochrane Review, Issue 4, 2002 4, 2002

• No evidence that LUNA adds value to No evidence that LUNA adds value to conservative surgery for conservative surgery for endometriosis associated pain.endometriosis associated pain.

Presacral neurectomyPresacral neurectomy

• Tjaden et al Obstet Gynecol 1990Tjaden et al Obstet Gynecol 1990– Value for midline pain at the time of mensesValue for midline pain at the time of menses– Few patients recruitedFew patients recruited

• Zullo F et al AJOG 2003;189:5-10Zullo F et al AJOG 2003;189:5-10– All stages of endometriosisAll stages of endometriosis– 141 patients double blind RCT141 patients double blind RCT– Improves the cure rate in women who are treated Improves the cure rate in women who are treated

with conservative surgery for severe dysmenorrhea with conservative surgery for severe dysmenorrhea caused by endometriosiscaused by endometriosis

– Constipation (14% at 12 months) & Urinary urgency Constipation (14% at 12 months) & Urinary urgency (5%)(5%)

Excision versus AblationExcision versus Ablation

• Pregnancy rates similarPregnancy rates similar

• Pain relief?Pain relief?

Rectosigmoid Endometriosis:Rectosigmoid Endometriosis:

• Significant bowel symptomsSignificant bowel symptoms

• Colonoscopy or barium enema Colonoscopy or barium enema normalnormal– May show a strictureMay show a stricture

• Persistent disease after TAH+BSO is Persistent disease after TAH+BSO is usually recto-sigmoid endometriosisusually recto-sigmoid endometriosis

Colo-rectal endometriosisColo-rectal endometriosis

• SuperficialSuperficial– PeritoneumPeritoneum– SerosaSerosa

• MuscularisMuscularis– Hypertrophy of muscle layerHypertrophy of muscle layer– Infiltration of levator musclesInfiltration of levator muscles

• MucosaMucosa– Uncommon to penetrate the mucosaUncommon to penetrate the mucosa

Rectosigmoid Endometriosis:Rectosigmoid Endometriosis:CCF experienceCCF experience

• Journal of the American College of Journal of the American College of Surgeons: Dec 2002Surgeons: Dec 2002

• 51 patients (32-39 years of age)51 patients (32-39 years of age)• Symptoms:Symptoms:

– Dysmenorrhea (85%), Dysmenorrhea (85%), dyspareunia(56%),rectal pain(41%),rectal dyspareunia(56%),rectal pain(41%),rectal bleeding(14%),bloating(29%), tenesmus(8%)bleeding(14%),bloating(29%), tenesmus(8%)

Surgical techniqueSurgical technique

• Excision of serosal implantsExcision of serosal implants

• Disc resection of infiltrating diseaseDisc resection of infiltrating disease

• Segmental Bowel resectionSegmental Bowel resection

Segmental Resection: Segmental Resection: Management of the proximal Management of the proximal

BowelBowel

• Exteriorize the proximal bowelExteriorize the proximal bowel– Trans-rectally ( no longer used)Trans-rectally ( no longer used)– Trans-vaginally (occasionally)Trans-vaginally (occasionally)– Mini-laparotomy (most common)Mini-laparotomy (most common)

• Disease removed & anvil placed for Disease removed & anvil placed for EEAEEA

OutcomeOutcome

• Operating time:187 minutesOperating time:187 minutes• LOS: 2 daysLOS: 2 days• No postop NG tube & all start oral fluids same dayNo postop NG tube & all start oral fluids same day• 1/3 patients outpatients1/3 patients outpatients• 7% conversion to laparotomy7% conversion to laparotomy• Complications: 4 patientsComplications: 4 patients

– 1 Pyosalpinx,1 leak, antibiotic associated diarrhea1 Pyosalpinx,1 leak, antibiotic associated diarrhea– 1 pneumonia1 pneumonia

Catamenial SciaticaCatamenial Sciatica

Diaphragmatic Diaphragmatic endometriosisendometriosis

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