Endometriosis -Why delay in diagnosis, ole of MRI & drug selection, mode of action of each drug.

Only YG: DNB due Introduction:--2-03-20

 What we need to know about endometriosis?? Why delay in diagnosis & dilemma in selecting the appropriate drug as per her symptoms

Endometriosis:- What are the symptoms? Why delay in diag?? Delay in diag is due to the fact that an endometriomata cause less  frequently a  palpable mass. When become a palpable mass like as we come across like  TO mass of infective origin.  Therefore, as things stand , whoever there is char pelvic pain if nothing can bane demonstrated we should consider endometriosis.=MRI is most helpful in clinically doubtful cases

Establishing the diagnosis of endometriosis on the basis of symptoms alone can be difficult because the presentation is so variable and there is considerable overlap with other conditions such as irritable bowel syndrome and pelvic inflammatory disease. As a result there is often a delay of several years between symptom onset and a definitive diagnosis .The following symptoms can be caused by endometriosis based on clinical and patient experience: severe dysmenorrhoea; deep dyspareunia; chronic pelvic pain; ovulation pain; cyclical or premenstrual symptoms (e.g. bowel or bladder associated) with or without abnormal bleeding; infertility; and chronic fatigue. However, the predictive value of any one symptom or set of symptoms remains uncertain as each of these symptoms can have other causes, and a significant proportion of affected women are asymptomatic. Substantial invasion in early stage when laparoscopic         detection is a least likely possibility Pelvic pain is more with deep infiltrating lesion and       histological evidence of lesion activity

Advanced stage structural changes would result in                 pressure on pelvic plexus of nerves

Superficial peritoneal endometriosis - sub-fertility by biochemical disruption of reproductive function  

Advanced stage structural changes would result                     in anovulation and poor egg pick up by tubes.

The following symptoms can be caused by endometriosis based on clinical and patient experience: severe dysmenorrhoea; deep dyspareunia; chronic pelvic pain; ovulation pain; cyclical or premenstrual symptoms (e.g. bowel or bladder associated) with or without abnormal bleeding; infertility; and chronic fatigue. However, the predictive value of any one symptom or set of symptoms remains uncertain as each of these symptoms can have other causes, and a significant proportion of affected women are asymptomatic.

Clinical signs-

Finding pelvic tenderness, a fixed retroverted uterus, tender uterosacral ligaments or enlarged ovaries on examination is suggestive of endometriosis. The diagnosis is more certain if deeply infiltrating nodules are found on the uterosacral ligaments or in the pouch of Douglas, and/or visible lesions are seen in the vagina or on the cervix. The findings may, however, be normal. It is a progressive and recurrent disease. Endometriosis is defined as the presence of endometrial-like tissue outside the uterus, which induces a chronic, inflammatory reaction. The condition is predominantly found in women of reproductive age, from all ethnic and social groups. The associated symptoms can impact on general physical, mental and social well-being. Therefore, it is vital to take careful note of the woman’s complaints, and to give her time to express her concerns and anxieties as in other chronic diseases. Some women, however, have A). No symptoms at all. It is true that “Guaranteed permanent cure is with TAH & BSO”      - not viable option or acceptable Tr for preserving fertility & hormone status. Diagnosis- How?

 The working group then ratified the guideline by unanimous or near-unanimous voting; finally, it was approved by the ESHRE Executive Committee. The guideline will be updated regularly, and will be made available athttp://www.endometriosis.org/guidelines.html with hyperlinks to the supporting evidence, and the relevant references and abstracts. For women presenting with symptoms suggestive of endometriosis, a definitive diagnosis of most forms of endometriosis requires visual inspection of the pelvis at laparoscopy as the ‘gold standard’ investigation. However, pain symptoms suggestive of the disease can be treated without a definitive diagnosis using a therapeutic trial of a hormonal drug to reduce menstrual flow. In women with laparoscopically confirmed disease, suppression of ovarian function for 6 months reduces endometriosis-associated pain; all hormonal drugs studied are equally effective although their side-effects and cost profiles differ. Ablation of endometriotic lesions reduces endometriosis-associated pain and the smallest effect is seen in patients with minimal disease; there is no evidence that also performing laparoscopic uterine nerve ablation (LUNA) is necessary.

Treatment are A) Medical B) surgery:-

Drawbacks of Medical Tr: _-“Recurrence is common after stopping medicine. Combined medical & surgical therapy is the most effective conservative approach for all stages.

Medical therapy comprises of 1)OCP,2)  Danazol and 3) GnRHa 4) Progestogen 5) Aromatase Inhibitors 6) NSAID . All  are equally effective in relieving pelvic pain but have different side effects and therefore vary in terms of compliance.

Comparison which drug to use?? OC pill is less expensive than Danazol & GnRHa but relapse is common immediately after stopping. GnRHa has much  side effects due to pseudomeopuase but side effects are less severe & manageable with add back  therapy in contrast to those with Danazol(very potent but have much side effects) . 4) Progestogen have safest clinical profile and most cost effective but not as effective as others  For Painful symptoms – No 6:L NSAID is best who don’t like to have restoration of fertility now, efficacy is similar to other drugs but the side effects are less and further reduced by the “add-back” HRT.

Ovarian endometrioma and rectovaginal endometriosis - drugs less effective except dienogest in small tumours

  If Subfertility  is the chief symptoms & role of drugs:- -Medl therapy has in fact  no role in stage I and II, but may be useful before ART in stage III and IV.

Those who come  with Painful symptoms & endometriosis: - In such cases the efficacy of NSAID  is similar to  other drugs but the side effects are less and further reduced minimal requirement by the “add-back” HRT.

Ovarian endometrioma and rectovaginal endometriosis - drugs less effective—But letrozole & OCP is worth trying.

By drugs trial:-women presenting with symptoms suggestive of endometriosis, a definitive diagnosis of most forms of endometriosis requires visual inspection of the pelvis at laparoscopy as the ‘gold standard’ investigation. However, pain symptoms suggestive of the disease can be treated without a definitive diagnosis using a therapeutic trial of a hormonal drug to reduce menstrual flow.

DIE: - Lap better: - Deeply infiltrating endometriotic nodules extend >5 mm beneath the peritoneum and may involve the uterosacral ligaments, vagina, bowel, bladder or ureter. The depth of infiltration is related to the type and severity of symptoms (Koninckx et al., 1991; Porpora et al., 1999; Chapron et al., 2003a).

The most commonly affected sites are the pelvic organs and peritoneum, although other parts of the body such as the lungs are occasionally affected. The extent of the disease varies from a few, small lesions on otherwise normal pelvic organs to large, ovarian endometriotic cysts (endometriomas) and/or extensive fibrosis and adhesion formation causing marked distortion of pelvic anatomy. Disease severity is assessed by simply describing the findings at surgery or quantitatively, using a classification system such as the one developed by the American Society for Reproductive Medicine (ASRM) (1997). There is no correlation between such systems and the type or severity of pain symptoms.

 C) New Serum Biomarkers for Detection of Endometriosis Using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry-Journal of International Medical Research (2011) 39 (4): 1184-1192

D) PET-CT :Evaluation of 18FDG PET-CT in the Diagnosis of Endometriosis: A Prospective Study-Reproductive Sciences (2011) 18 (6): 540-544

Treatment Plan: Treatment must be individualized, taking the clinical problem in its entirety into account, including the impact of the disease and the effect of its treatment on quality of life. B).Pain symptoms may persist despite seemingly adequate medical and/or surgical treatment of the disease. In such circumstances, a multi-disciplinary approach involving a pain clinic and counseling should be considered early in the treatment plan. It is also important to involve the woman in all decisions; to be flexible in diagnostic and therapeutic thinking; to maintain a good relationship with the woman, and to seek advice where appropriate from more experienced colleagues or refer the woman to a centre with the necessary expertise to offer all available treatments in a multi-disciplinary context, including advanced laparoscopic surgery and laparotomy. The guideline was commissioned by the ESHRE Special Interest Group (SIG) on Endometriosis and Endometrium, and developed by a working group. No systematic attempt was made to search the published literature independently of the following sources

ESHRE guideline: management of women with endometriosis (Hum Reprod (2014) 29 (3): 400-412).Consensus on current management of endometriosis Hum Reprod (2013) 28 (6): 1552-1568.Treatment must be individualized, taking the clinical problem in its entirety into account, including the impact of the disease and the effect of its treatment on quality of life.

Take home message:Role of Pain management Experts & Flexibility of prescribing Gynaecologists:--Treatment must be individualized, taking the clinical problem in its entirety into account, including the impact of the disease and the effect of its treatment on quality of life. Pain symptoms may persist despite seemingly adequate medical and/or surgical treatment of the disease. In such circumstances, a multi-disciplinary approach involving a pain clinic and counselling should be considered early in the treatment plan. It is also important to involve the woman in all decisions; to be flexible in diagnostic and therapeutic thinking; to maintain a good relationship with the woman, and to seek advice where appropriate from more experienced colleagues or refer the woman to a centre with the necessary expertise to offer all available treatments in a multi-disciplinary context, including advanced laparoscopic surgery and laparotomy.

Treatment of endometriosis-associated pain  A) NSAID:-In confirmed disease Non-steroidal anti-inflammatory drugs. It is important to note that NSAIDs have significant side-effects, including gastric ulceration and an anti-ovulatory effect when taken at mid-cycle. Other analgesics may be effective but there is insufficient evidence to make recommendations.

B). Hormonal treatment: The levonorgestrel intrauterine system (LNG-IUS) may be effective at reducing endometriosis-associated pain (Vercellini et al., 1999a), but there is insufficient evidence to make recommendations.

 C) Duration of GnRH agonist treatment 

Surgical treatment” There are no data to justify hormonal treatment prior to surgery to improve the success of surgery (Muzii et al., 1996).There are no data supporting the use of uterine suspension but, in certain cases, there may be a role for pre-sacral neurectomy (Soysal et al., 2003). Medications to control pain

Medications to stop the endometriosis from getting worse

Surgery to remove the areas of endometriosis

Hysterectomy with removal of both ovaries

Post-operative treatment

Hormone replacement therapy

Treatment of endometriosis-associated infertility in confirmed disease
Treatment of endometriotic lesions

B).Pain symptoms may persist despite seemingly adequate medical and/or surgical treatment of the disease. In such circumstances, a multi-disciplinary approach involving a pain clinic and counseling should be considered early in the treatment plan. It is also important to involve the woman in all decisions; to be flexible in diagnostic and therapeutic thinking; to maintain a good relationship with the woman, and to seek advice where appropriate from more experienced colleagues or refer the woman to a centre with the necessary expertise to offer all available treatments in a multi-disciplinary context, including advanced laparoscopic surgery and laparotomy. The guideline was commissioned by the ESHRE Special Interest Group (SIG) on Endometriosis and Endometrium, and developed by a working group. No systematic attempt was made to search the published literature independently of the following sources:

List of Drugs:-

Oestrogen dependant condition and regress during amenorrhoea: pregnancy, menopause, Medical therapy, Individual choice Age - young women are suitable for OC pill, Symptom of patients - pain or subfertility, ,Side effects of drugs - oestrogen deficiency, androgen excess

Recurrence of symptoms after a therapy, Economic status of the patient - OC pill cheaper Peritoneal and superficial ovarian lesions 

Deep infiltrating lesions - bladder, rectum, rectovaginal septum    : poor response

Endometrioma: sub-optimum response...Endometriosis is not a single disease in      

 Terms of it appearance and histology        ,

A)   Agents suppressing menstruation: 1) OCP, 2) Progestogen

B)   Agents lowering serum oestrogen: 3) Danazol, 4) GnRH-a,5)  Aromatase over expression           increased conversion of Androgen to Oestrogen

C)   Increased Cyclo-Oxygenase - 2 (COX-2), COX -2 inhibitor (Celecoxib, Roficoxib, WE have to keep in mind that it is the increased PGE2 synthesis causing pain, Deficiency of 17 beta OH dehydrogenase – 2,, impaired Oestradiol to Oestrone conversion ,

D) Newer treatment for Endometriosis is Aromatase inhibitor (Letrozole)

) O C pills Activin A regulates trophoblast cell

adhesive properties: implications for

implantation failure in women with

endometriosis-associated infertility

Chelsea J. Stoics 1 , Lois A. Salamonsen 2 , Natalie J. Hannan 2 ,

Anne E. O’Connor 3 , Luk Rombauts 1 , and Evdokia Dimitriadis 2, *

1

Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3800, Australia 2 Prince Henry’s Institute of Medical Research,

PO Box 5152, Clayton, VIC 3168, Australia 3 Monash Institute of Medical Research, Clayton, VIC 3168, Australia

*Correspondence address. Fax:+61-3-9594-6125; E-mail: evdokia.dimitriadis@princehenrys.org

Submitted on October 19, 2009; resubmitted on March 10, 2010; accepted on March 23, 2010

Progestogen,

Danazol

Gestrinone

GnRH analogues Hypo oestrogen,   Amenorrhoea, arrest, regression, degeneration and           ? Disappearance of endometriosis

                        Symptom relief

Accomplish complete destruction of disease

Treatment of microscopic or metastatic disease

Helps in incomplete extirpation of disease

Effective in severe refractory pelvic pain

Improves outcome in large ovarian endometrioma. Risk of recurrence after GnRH-a in 5 years: 53% Minimal 37%     ,,advanced 74% , alter & Shaw (1993) F & S, Repeat, GnRH-a for 3-6 months is effective & safe      ,Adamson (1997) Am J O & G. Hornstein (1997) F & S  patients with pain should be treated aggressively  by adjuvant medical therapy with GnRH even     after conservative surgical excision or ablation 

Early disease is immunologically more active, deficient immunological defense mechanism

Suppresses immunological effect of disease, Disease is certainly more extensive than detected       by laparoscopy at the time of surgical staging; Disease recurs less frequently and less rapidly      .

New Medl management of Endometriosis.-Fourth generation progesterone:  Dienogest

Q.1.What is Dienogest?

Dienogest, a synthetic progestin.

 Q.2. what is the dose of Dienogest?

The dose recommend is minimum 2 mg OD but can be given up to 10 mg. To b given for 6 moths .Dienogest is definitely effective in dysmenorrhea associated with endometriosis.

Q.5. can Dienogest cause BTB? Yes, it may cause irregular spotting.

Q.6. Can it be used to control AUB –It is not used in, particularly bleeding phase of AUB.

Q.9. is it possible to give cyclic Dienogest & GnRH agonists? Many people use GnRH for six months followed by Dienogest for 6 months. Dienogest gives good results in 50 % cases of endometriosis. In the other 50 % it does not work at all. So no harm in trying dysmenorrhea, women with chocolate cysts, menorrhagia associated with endometriosis, & Adenomyosis. .

10. Role of Dienogest in recurrent implantation failure with cases of Adenomyosis?  In cases with adenomyosis pretreatment with Dienogest: - rather, now it is the first line drug for me in Adenomyosis related implantation failure.

Q.13. it can also be used at post operative period-Top of Form

Q.11. is it useful in Myoma? Possibly not.

Q.11.Is Dienogest a contraceptive? Dienogest has been used as a contraceptive with estrogen for years. As only progesterone it is new. Irregular bleeding is a side effect possibly not.  Pregnancy can occur while on therapy:--while on Dienogest:-One of my pt of bilateral endometriomas 5cm was advised surgery for secondary infertility. I had put her on Dienogest. She is pregnant for 4 months. She developed Amenorrhea. Now she is 16 weeks pregnant. USG is normal. Her ovaries have reduced in size Natural estrogens with Dienogest are QLARIA .Dienogest with natural Oestrogen containing OCP.

 Dienogest with Natural oestrogen

 . Progesterone Receptor Modulators

: - Dienogest. 1) The side effects of Visanne (Dienogest-Bayer) are Chloasma, depression, irregular bleeding, ovarian cyst formation. Wt Gain, Nausea.  I don’t know how this young adolescent girl will react to any such side effect, if at all occurs to her.  I am not against such drug in this case. Will 1 mg dose (anovulatory doe) will be able to manage endometriosis.  Will combination of Dienogest with natural   Oestrogen will be at all effective to control endometriosis, keeping in mind that the very diagnosis has not been confirmed in this case. The idea of prescribing Dienogest containing natural oestrogens  stems from the fact such drugs will ensure monthly bleeds & possibly assure this girl(I call her girl)  that all is well. I understand many gynaecologists will purposefully intend to avoid EE (synthetic agent) which is very potent and will exert more harmful effect on the existing pathology (endometriosis).

Such combinations of natural oestrogens with Dienogest are QLARIA –polyphonic preparations (marketed again by Bayer) and the Oestro component used is E2V (valerate). The other trade names are Klaira, Natazia. –all quadriphasic.

I appeal some ART specialist to consider for trial on couple of cases particularly in women where fertility is not an issue (therefore no question of loosing time to conception – post Tubectomy endometriosis).    Bayer Co. / Endometriosis Society of India/. FOGSI can help in funding if may

E2 valerate with Dienogest as progesterone as OCP:-Brand names are :-Klaira, Natazia. –all quadriphasic

D). Progesterone Receptor Modulators

I am not pessimistic on Dienogest nither one should be under the impression I disagree with usefulness of such drug in the present scenario. Facts to be kept in mind are: - 1) the side effects of Visanne (Dienogest-Bayer) are Chloasma, depression, irregular bleeding, ovarian cyst formation. Wt Gain, Nausea.

 I don’t know how this young adolescent girl will react to any such side effect, if at all occurs to her.  I am not against such drug in this case. Will 1 mg dose (anovulatory doe) will be able to manage endometriosis.  Will combination of Dienogest with natural   Oestrogen will be at all effective to control endometriosis, keeping in mind that the very diagnosis has not been confirmed in this case.

The idea of prescribing Dienogest containing natural oestrogens stems from the fact such drugs will ensure monthly bleeds. I understand many gynaecologists will purposefully intend to avoid EE (synthetic agent) which is very potent and will exert more harmful effect on the existing pathology (endometriosis).

Such combinations of natural oestrogens with Dienogest are QLARIA –polyphonic preparations (marketed again by Bayer) and the Oestro component used is E2V (valerate). The other trade names are Klaira, Natazia. –all quadriphasic.

I appeal some ART specialist to consider for trial on couple of cases particularly in women where fertility is not an issue (therefore no question of loosing time to conception – post Tubectomy endometriosis).    Bayer Co. / Endometriosis Society of India/. FOGSI can help in funding if may be approached.

What about other Progesterone Receptor Modulators in this young adult?   Will any Indian Doctor become team leader in study of ULIPRISTAL ACETATE (UPA) in Pel?

Endometriosis.

Ulipristal as ECP.

It is an FDA approved drug for Emergency contraceptive used as 30 mg single dose as post coital contraceptive (Morning after pill). Research has confirmed that ULIPRISTAL ACETATE (UPA) is more effective that LNG 1.5 mg. The trade name is Ella One. –Regarding the apprehension raised by members about the use of  minipills progesterones( though WHO has referred to LNG and not specially to Dienogest) or even COC in a case impaired hepatic function (fatty liver/ NAFL- non-alcoholic fatty liver) :---- may I draw attention to the fact that WHO medical Eligibility criteria put use of LNG as category  2 risk  only in cases with 1) Non vascular DM    2) DM with nephropathy      3) P/H/O preg Cholestasis (cat 1 risk-no risk)/ past COC related Cholestasis(Cat 2 risk    4)  Acute viral hepatitis  ! (Not to speak of Chr carriers)  -believe me I am quoting from original WHO BOOK, Ed. 2010, ISBN 978 92 4 15388 8) p. 53       5) Valvular heart disease     ) Multiple risk factors for arterial CVS disease (!)  7) Controlled HTN with drugs. ) no age bar 9) Smokers of all ages (!). 10) Obese women 110 DVT on oral anticoagulants (!) & Myomas.

Such views have also been expressed by other academic bodies like Clinical Guidance. Contraception for women aged over 40 yrs by UK, Australia and USA separately.

 I am not very sure whether such liberal use will be safe for Dienogest too. 3) Another issue- The compulsion of use of a drug for treating disuse as using Dienogest cannot be equated to contraceptive prophylaxis where other options are available.

Again ICMR and its control Six population research centres, “Human Reproductive Research centres” = Total such centres are 31 in India,  20 ICMR study centres can forward to ace o pilot study on this issue. ENDOETRIOSIS is a nightmare to ART specialists!!!

Dose used as selection of type of progesterone.

Minimal to mild endometriosis

            GnRH / Danazol / Gestrinone / MPA / Placebo

                  No improvement in pregnancy rate

            Henzl (1988); Dmowski (1989); Fedele (1989);     Fraser (1991); Fedele (1992); NEETG (1992)

Moderate to severe endometriosis

            No evidence to support medical therapy

            Delays more effective surgical treatment

                          Oehninger (1990); Dicker (   Women who wish to maintain fertility potential - GnRHa has a special role to play after Endometriosis surgery

Successful in preventing adhesions – most critical complication even after Laparoscopic Endometriosis surgery.

Side effects of Diff Medl TR schedules for Endometriosis:-

What side effects associated with  OC pill / Progestogen?,:-a) Irregular vaginal bleeding)  nausea, c) headache, d) breast, tenderness, e)fluid retention, 9) weight gain, 10)depression

What side effects with Danazol / Gestrinone??      weight gain, muscle cramps, decreased breast size, oily skin, acne, irregular vaginal bleeding, oedema,        mood changes, depression, fatigue, hirsutism, loss          of libido, adverse lipoprotein effect, liver toxicity

GnRH analogues;                      Hot flushes, vaginal dryness, irregular vaginal bleeding,        decreased libido, irritability, fatigue, headache, insomnia,    depression, joint stiffness, osteopenia /osteoporosis.

Add Back Therapy.

Oestradiol valerate 2mg + Norethisterone 1mg

Oestradiol patch 25mcg + MPA 5mg

Conjugated E 0.625mg + MPA 5mg

Norethisterone 5 mg   M P A 20 - 30mg

Tibolone 2.5mg       •  Alendronate 10mg Lesser or no reduction in bone mineral density

Absence of oestrogen deficiency symptoms        

No influence on pain relief and r-AFS scores        

Benefit persists up to 48 weeks after therapy

Safely extends the use of GnRH-a therapy                              

HRT is safe
 Post menopausal women

After Hysterectomy 4 groups of women

Oestrogen

Oestrogen + Cyclical Progestogen

Oestrogen + Continuous Progestogen

Control

2% recurrence only in Oestrogen group

Androgen has therapeutic effect on Endometriosis Tibolone is therefore an effective choice                                

Summary of AVAILABLE agents for endometriosis: List of Drugs:--

OCP   2) Danazol-Gonablock / Zendol,    3) Add back low dose Oestrogen, 4)  Dienogest- Endopreg,(Jags son Pal), Endosis( Pharma Nova) ; Endoheal-Akumentis ,  2 mg 5) Endofine ( Akumentis-  1 tab BD. 15/- per Tab; 6) Adova  1mg OD –but peripheral production of E2 will continue 7) Inj Goserelin-3.6 mg on monthly basis.8) Ulipristal- / Asoprisnil Drugs targeted at the immune site are  better,  9)  Cabgolin-0.5 mg twice a week  10)  AISR—(Cnidus Apex)- Reversatol 25 mg OD. –Benfotiamine- 50 mg,   L-Carnitine, Vit B6, 11) locally acting drugs are better more specific-Mol basis of Endometriosis, - 12) Mifepristone 50 mg OD 13) NSAID, 14) LNG-IUS 15) SPRM-

 Details of Progesterone Receptor Modulators

4 types-Mifepristone, Adova, and Asoprisnil Ulipristal-> ULIPRISTAL ACETATE AS Endometriosis

The trade name is EllaOne...  16) Depo-/ Tab MPA.17) Immuno modulators 18) Antioxidants-

Combined Drugs –Two Drugs at a time.

Combined Agonists & along with Adova.,,Use drugs by Rotation: - Agonists, Agonists with Adova, Dienogest, NSAID,, Follow up if HP Suppressors are used BMD of L1-L4 vertebra.-

Treatment those seeking infertility.

minimal or mild endometriosis: -- If the endometriosis is minimal or mild (based on the ASRM* classification), there is no significant ovulatory abnormality, there is no male factor, the duration of the infertility is less than a year or two, and the woman is under 30 years of age, waiting 3-6 months to see if a spontaneous conception will occur is an option. However, more aggressive therapy using Super-Ovulation combined with IUI will significantly increase the woman's chances of becoming pregnant...: Laparoscopy performed after six cycles of unsuccessful IUI did not detect more abnormalities with clinical consequences compared with those performed prior to IUI treatment. Our data suggest that the impact of the detection and the laparoscopic treatment of observed pelvic pathology prior to IUI seem negligible in terms of IUI outcome. Therefore, we seriously question the value of routinely performing a diagnostic and/or therapeutic laparoscopy prior to IUI treatment. Further prospective studies could be performed to determine the effect of laparoscopic interventions on the success rate of IUI treatment in order to rule out completely the laparoscopy from the diagnostic route prior to IUI.

Key words

1B) if the endometriosis is minimal or mild and the duration of the infertility is more than two years, the treatment of choice is Superovulation with Intra-Uterine Insemination. Gonadotropin therapy is the best treatment unless you are covered by an HMO or other insurance which does not pay for these drugs. In such instances, Clomiphene must be used. The results are not as good as with Gonadotropin therapy, but better than no therapy at all. If the endometriosis is low in the moderate range, a surgical laparoscopy followed by the institution of Superovulation therapy with IUI, is the treatment of choice.

2) If the endometriosis is high in the moderate range (according to the ASRM classification), a surgical laparoscopy followed by 6 months of GnRH followed by Superovulation with IUI is the best approach. If the endometriosis is severe, a laser laparoscopy will be performed. Following this several months of GnRH (Lupron or Synarel) suppression is instituted followed by a second look laparoscopy. After the second look laparoscopy, the GnRH suppression is maintained until the woman has been on the drug for a total of six months. Following this, Superovulation with IUI is instituted. However, I have had many women conceive without additional therapy following this treatment regimen,

2B) Endometriosis is very severe (ASRM score > 70, after the initial laparoscopy which assesses the severity of the disease, the woman should go on GnRH suppression for 2-3 months, followed by open surgery, If the Endometriosis is very severe (ASRM score > 70), the disease is frequently too expensive to safely and (more importantly) appropriately treat by laparoscopy. In such instances, after the initial laparoscopy which assesses the severity of the disease, the woman should go on GnRH suppression for 2-3 months, followed by open surgery, followed by a second look laparoscopy. The GnRH is maintained for a total of 6 months. Section III - Future Pregnancy Is Not a Consideration

If a woman is not interested in preserving or enhancing her future fertility, a laparoscopy must still be carried out to establish a definitive diagnosis and "stage" the disease. The following therapies should then be offered. Following the laparoscopy, the woman should go on GnRH suppression for a period of three to six months. This is done because the GnRH suppression mimics the effect of a hysterectomy. Hysterectomy is the definitive treatment for most women with significantly symptomatic endometriosis.

Conservation of Ovaries in TAH if needed for Endometriosis. Ovarian Removal

.

If the hysterectomy has been performed for endometriosis or other problems, the arguments are less clear. There is still a debate and the issue may never be completely resolved. I would like to give you at this time my personal opinion and the reasons why I believe what I do. However, it is still a matter of choice for the woman in most instances. Newer advances in medicine have also forced a reappraisal and the issue is far from settled. In summary, I am more and more leaning toward ovarian conservation, especially in younger women. Yes, it is a calculated risk, especially if the hysterectomy is done for Endometriosis. There is the risk of needing additional surgery. Nonetheless, the problems associated with a significant decrease in libido can be as devastating as the possibility of another operation. Each woman must decide for herself

The ovary has 2 principal functions - the making of eggs and the making of estrogen. Obviously, both are necessary for the woman to have children. Once the uterus has been removed, the reproductive capability of that woman is usually no longer a consideration and therefore, only the ovary's hormone production is of significance. I am not aware of any scientific evidence that the estrogen produced by the woman's ovaries, if they are left in place, is any better for her than the estrogen she would take by mouth if the ovaries were removed.

What about Androgen produced from Ovaries—Replacement?

However, the ovaries produce other hormones beside estrogen. The other main hormone produced by the ovary is androgen - male hormone. In fact, the ovary continues to produce significant amounts of androgen after menopause, even though estrogen production decreases. Also, in addition to estrogen, the ovary makes male hormone (androgen) which we know is the hormone responsible for your sex drive. I have seen women who suffered a noticeable loss of sexual desire and sexual response following hysterectomy with removal of the ovaries at a younger age (under 40). Occasionally, even older women will notice a decrease in libido when their ovaries are removed. Furthermore, most of these were women undergoing hysterectomy for endometriosis so that 1) removal of the ovaries was advisable and 2) they had no regrets concerning their surgery since their pelvic pain and other symptoms were relieved.

Admittedly, for years we minimized or ignored the significance of the ovarian androgen production. Now, however, evidence is that the androgens are beneficial and that women will do better if their ovaries are left in place. Certainly, in some women, a normal sex drive is dependent on ovarian androgen production. This is not to say that there a compelling reasons to remove the ovaries in some women. Each woman must be assessed individually and the best decision for her made. First of all, it is actually technically easier to remove the ovaries that it is to leave them in place, notwithstanding a common myth to the contrary. While this is not a major factor, it is nonetheless true. Furthermore, an ovary left in place may become adherent to the side of the pelvis or to the top of the vagina. In such instances, it can produce considerable pain.

Long term problems if Ovaries are preserved in TAH.

Firstly, 3-5 % of women who undergo hysterectomy in which the ovaries are left will subsequently undergo surgery to remove those ovaries. If a woman has a hysterectomy for endometriosis and the ovaries are left, she has a 50% chance of requiring surgery within 5 years. Nonetheless, if that woman is young, it may be better to leave at least one ovary and take a chance.

Reduction of Ca Breast, Ca Cx, if TAH done.

If a woman undergoes removal of her ovaries before the age of 35, her chances of subsequently developing breast cancer are reduced. One out of 9 women in this country will develop breast cancer over her lifetime. If a woman has her ovaries removed at a young age, this will reduce her risk. If the woman has a strong family history of breast cancer, I personally believe that if she has a reason for hysterectomy, removal of the ovaries should be strongly considered.
The most common cancer of the female reproductive tract is cervical cancer and the second most common cancer is uterine cancer. Cancer of the ovary is number three. However, we have good diagnostic and therapeutic measures for cervical and uterine cancer. Therefore, our ability to cure women of these two malignancies is good. On the other hand, we do not have a good early warning system for ovarian cancer and, therefore, although ovarian cancer is number three in frequency, ovarian cancer is the leading cause of death from pelvic malignancy. Removal of the ovaries at the time of hysterectomy at least insures that women that she need never worry about ovarian cancer. There is no significant risk to taking estrogen after menopause despite all that you might read or see on TV. There is without question a significant decreased risk of osteoporosis, major fractures, and heart disease in women who receive estrogen therapy following menopause. There is increasing evidence that estrogen reduces the risk of colon cancer and Alzheimer's disease. Estrogen therapy probably reduces the risk of developing cataracts. Women who take estrogen live longer, healthier lives.