Harvey S. Marchbein, MD

Endometriosis - defined as the presence of endometrial-like glands and stroma in any extrauterine site - is a common disease occurring in 7-10% of all women, and is often associated with chronic pelvic pain and infertility. Apart from these significant individual problems women with endometriosis and their families may face, this disease has a significant impact our society due to its chronic nature 

The symptoms of endometrioses are variable and its course is often unpredictable. While some women may be asymptomatic, the most common manifestations are pelvic pain, particularly with periods, dispaureunia, pain associated with bowel movements, and dysuria or hematuria in cases of bladder involvement.  Despite significant improvements in understanding of this disease, the pathogenesis of endometriosis remains unclear. There are several theories that were suggested; most prominent includes theory of retrograde menstruation associated potentially with genetic susceptibility for the disease. Also theories of hematogeneous and/or lymphogenic spread, genetic link, or defects in immunocompetency have been suggested

The link between endometriosis and ovarian cancer is well recognized and has perplexed physicians for a long time 

. Epidemiological studies have suggested a specific link with endometrioid and clear-cell ovarian cancers, but no firm evidence established endometriosis as an ovarian cancer precursor lesion. Several lines of clinical evidence have supported the observation that non-serous ovarian carcinomas such as endometrioid and clear-cell carcinomas arising from atypical endometriotic foci have a higher likelihood of early diagnosis, as the associated endometriosis can cause pelvic pain or infertility requiring specialized gynecologic care including diagnostic laparoscopy. Deligdisch et al. reported a series of 76 cases of stage I ovarian carcinomas and documented that non-serous carcinomas (54/76) were diagnosed because of the associated symptoms including pelvic pain associated with endometriosis or vaginal bleeding associated with hyperestrogenism and endometrial pathology

. Interestingly they also found that serous carcinomas were frequently found in asymptomatic women with breast cancer diagnoses 

. These and similar observations support the emerging dual model of ovarian carcinogenesis. According to this model, Type I cancers are low grade, slowly developing ovarian carcinomas (including endometrioid, mucinous and low grade serous) associated with KRAS, BRAF, PTEN and B-catenin mutations and often associated with endometriosis. Type 2 is high-grade serous carcinomas associated with TP53 mutations that develop rapidly, are more aggressive and their origin is now thought to be tubal epithelium 

In the recent remarkable study reported in Lancet Oncology, the team of researchers from the Ovarian Cancer Association Consortium (OCAC) performed pooled analysis of 13 case-control studies and confirmed that women with self-reported history of endometriosis have significantly increased of clear cell carcinoma (odds ratio 3.05) and endometrioid ovarian cancer (odds ratio 2.04) 

. In addition the authors show, for the first time, that endometriosis is associated low-grade serous ovarian carcinomas, doubling its risk in women with endometriosis

.  However, there was no association between endometriosis and high-grade serous carcinomas or other subtypes of ovarian cancer in the study.

Taken together these findings will have considerable clinical implications and may affect the ways we think about strategies for ovarian cancer screening and prevention. In particular, the emerging knowledge of the link between ovarian cancer and endometriosis gives us an unprecedented opportunity to develop comprehensive screening plans to aid in the early detection and prevention of specific types of ovarian cancer in women with endometriosis. Such planning should include:

1) Identification of all women with endometriosis – either surgically documented or self-reported by symptoms;

2) Careful  follow up of ovarian presumed endometriomas by imaging studies, perhaps by MRI, for any characteristics changes such as mural formation;

3) Complete surgical resection of all endometriotic foci in women undergoing surgical treatment and tissue evaluation of ovarian endometriomas to rule out malignancy;

4) Hormonal treatment aimed at reducing the risk of cancer in high-risk women.

While it is well known that most women with endometriosis do not develop ovarian cancer, the women and their physicians should always discuss these new findings, carefully document and discuss any new symptoms and formulate plan for regular evaluations and treatment.


1. Simoens S, Hummelshoj L, D’Hooghe T. Endometriosis-cost estimates and methotologic perspective. 

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2. Burney RO, Giudice LC: The Pathogenesis of Endometriosis. In Nezhat C, Nezhat F, Nezhat C, (eds): Nezhat’s Operative Gynecologic Laparoscopy and Hysteroscopy. 

New York, New York: Cambridge University Press

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3. Munksgaard PS, Blaakaer J. The association between endometriosis and ovarian cancer: a review of histological, genetic and molecular alterations. 

 2012;124:164-69.
4. Nezhat F, Datta MS, Hanson V, et al. The relationship of endometriosis and ovarian malignancy: a review. 

 2008;90:1559-70.
5. Deligdisch L, PÃ©nault-Llorca F, Schlosshauer P, et al. Stage I ovarian carcinoma: different clinical pathologic patterns. 

 2007;88:906-10. 6. Levanon K, Crum C, Drapkin R. New insights into the pathogenesis of serous ovarian cancer and its clinical impact. 

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7. Pearce CL, Templeman C, Rossing MA, et al. on behalf of the Ovarian Cancer Association Consortium. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. 

Articles

Emerging information on the link between ovarian cancer and endometriosis gives us an unprecedented opportunity to develop comprehensive screening plans for early detection and prevention of specific types of ovarian cancer.

Endometriosis and Risk of Ovarian Cancer: An update

 A Novel Device for Peritoneal Access in Laparoscopic Surgery

"Safe abdominal entry and prevention of retroperitoneal vascular  injuries during laparoscopic surgery are the ultimate goals of any  laparoscopic surgeon.  Dr. Linda Nicoll and colleagues very capably have  been able to describe a new technique and technology that prevent  almost all retroperitoneal vascular injuries during laparoscopic entry."

 -    Linda M. Nicoll MD, Madelein Lemyre MD, Dorian Bosev MD, Jian Qun Huang MD, Lisa Bhagan MD and Camran Nezhat MD

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           Editor-in-Chief
 "New Frontiers in Reproductive Medicine"
           OBGYN.net

afe abdominal entry and prevention of retroperitoneal vascular injuries during laparoscopic surgery are the ultimate goals of any laparoscopic surgeon.  Dr. Linda Nicoll and colleagues very capably have been able to describe a new technique and technology that prevent almost all retroperitoneal vascular injuries during laparoscopic entry.

Frontiers in Reproductive Medicine

 I developed Osteoporosis from taking Lupron for seven months. (To treat Endometriosis. I took 3.75mg monthly). My doctor put me on Fosamax, 5mg daily for the first month, and then 10mg daily for another 5 months. Is this treatment adequate, or should I have taken Fosamax for a longer period? If so, what is recommended? Also, at what point should the bone density test be repeated?

 My first thought is as to whether or not add back therapy was used to prevent the osteoporosis that can accompany prolonged GnRH therapy. The reason for therapy with Lupron was not mentioned so the point is one of academic interest but not practical at this time.

Fosamax 10mg daily is an adequate dose but the duration of therapy has to be customized to the level of osteoporosis and the speed of return to normal density levels. This is variable. During therapy, a urinary NTX could have been done to insure reduced bone turnover and it can still be done now, after therapy, to confirm premenopausal NTX levels if you, indeed, are premenopausal (not mentioned above).

Osteoporosis is frequently reversible in premenopausal women with adequate Calcium supplementation and weight bearing exercise because endogenous circulating estrogen should be helpful in and of itself. An important point is that we don't know your pre-treatment bone density or physical exam or family history which may also impact on your recent bone density.

The duration of therapy can not be determined in advance so that question is unanswerable. The repeat bone density should not be done earlier than 12 months and many experts recommend 24 months at a minimum due to variability of measurements even in the same person on the same machine on the same day (2-3% variation noted).

I have been diagnosed with Osteoporosis. I am a 60-year-old Caucasian female. I have not had a hysterectomy. I have been talking Ogen and Provera for the past five years. Can/should Fosamax be used in conjunction with HRT to help rebuild bone density?

If this is your first bone density, we have no way of knowing if there has been a decrease in bone density despite HRT (18% of women are genetically incapable of building bone from being on HRT) or if your bone density was always low and the HRT is keeping it stable.

Fosamax can be used in combination with HRT although there are very few papers in the literature at this point, indicating this. Anecdotally, this has been a very effective combination.

Another option is to get a urinary NTX prior to adding medication to determine the bone turnover and see if additional therapy is warranted at this time. Therapeutic modalities will also depend upon the severity of osteoporosis shown on the bone density.

Some small amount of literature speaks about HRT with the addition of small amounts of androgen to increase bone production. Pros and cons of adding this therapy should be discussed with your physician.

 I have an 81 year old female patient who is taking Calcium, ERT (Premarin, .625mg), (s/p hysterectomy), and has taken Fosamax for 3 years for a history of lumbar compression fractures. I ordered her first bone density study, DEXA, which showed Z-scores (compared to young adult) of lumbar: -0.83, hip: -1.87, and radius -3.54. Should her therapy be changed?

 T scores are compared to young adults. Z scores are compared to patients of the same age. I wonder if there is degenerative joint disease along with compression falsely increasing the lumbar reading because that is not consistent with osteoporosis causing vertebral fractures.

Due to history of vertebral fractures, treatment should be maintained. A urinary NTX can be obtained to determine bone turnover to insure adequacy of therapy.

 Should Fosamax be used longer than 3 years?

 No reason why it can't. May depend upon the bone density and what it changes to in that 3 year period.

Regarding the reporting form for DEXA Densitometry , specifically the LUNAR brand

 What is the significance of >2.5 S.D. over young adult values at the distal radius, if the 33% value is normal, and why is this reported?

 For the spine, is the L1-L4 the best marker? Is this an average? Are all values given, in case 1 or 2 are markedly different from osteoarthritis or other disorder, and we should thus not use them in our interpretation?

 Both the separate values and the average are important. With osteoarthritis, the value will be abnormally elevated, making an osteoporotic vertebra appear better than it is and a normal vertebra may have a positive T score indicative of degenerative joint disease.

 For the hip, I have been told that the Wards triangle value is useless, and the only one to pay attention to is the neck value. If so, why are 3 values reported?

 Wartd's traingle is of limited value because there is no agreement on *exactly* where on the bone densitometry Ward's triangle is. The neck has been shown to be the most reliable value. The 3 values are reported as a matter of custom and hopefully, in the future this will be changed by the NOF (National Oseoporosis Foundation or another governing body.

 What do I tell a patient who has very discrepant values from radius to hip to spine, for example, +.09, -2.5, and -0.85, and what is the significance of which bone is the lowest in density?

 You tell the patient she has osteoporosis evident in the hip and considering the mortality associated with hip fracture, treatment is recommended.

 If I have a bone density value in g/cm2 from a SPA study can I compare that value to a subsequent DEXA value?

 My understanding is that only DEXAs can be compared to DEXAs and even that is not completely true due to variations from one machine to another.

Questions by Kathleen Griffin, M.D. Maui, Hawaii
 Answers by Harvey Marchbein, M.D. Great Neck, New York

 I have an 81 year old female patient who is taking Calcium, ERT (Premarin, .625mg), (s/p hysterectomy), and has taken Fosamax for 3 years for a history of lumbar compression fractures. I ordered her first bone density study, DEXA, which showed Z-scores (compared to young adult) of lumbar: -0.83, hip: -1.87, and radius -3.54.
 Should her therapy be changed?

Questions answered by Harvey S. Marchbein, MD

Osteoporosis Ask the Expert

I am a 45 year old white female that was just diagnosed with 	osteoporsis. (-3.9 below the mean, which I'm told is severe). I had a hysterectomy at age 28 with no estrogen supplements. 	Because of cancer in my immediate family, estrogens are out of the question now. I am currently take Evista along 	with 1500 mg calicum w/vitiman D.

Depending upon the cancer and who in the family had the cancer (in addition to what year this information was imparted) this may or may not still be true. Unfortunately, Evista is not approved for osteoporosis and is no better than low dose estrogen or low dose Fosamax, so many experts would consider this insufficient therapy for your osteoporosis.

I have a t-5 compression that is 10yr old but is giving me 	alot of pain in the form of spasms. My doctor wants to do a nerve block but I insisted on therapy, hot packs , 	ultra sound and stim. My therapist wants me to do upper back exercises on the machines. Two doctors have told me 	to do nothing but walk. I'm confused and scared to even pick up my grandchild in case I should break a bone. How 	careful do I have to be? I'm afraid to do anything. Please help. Thank you, debbie

Many therapies can have similar, positive effects. Keeping that in mind, we always try to do the least invasive treatments fo a particular situation. Your questions might be best answered by a rheumatologist with a special interest in osteoporosis or an Osteoporosis Clinic at a University Hospital. they are somewhat too specific for this forum.

Does having twins at age 39 predispose the mother to osteoporosis? 	(I had my first child at age 25).

If appropriate calcium intake was observed and the patient has no other predisposing factors, the answer is *no more than any other 39 year old*.

Your case has too many variables and too little specific information for exact therapeutic recommendations, but some comments should be made.

I am a 45 year old who consumes little to no dietary calcium, 	and I have a strong family history of osteoporosis.

That is one thing that you can easily do and needs to be corrected immediately. Vitamin D is also needed in adequate amount.

My gynecologist did an osteoscan at my request this past 	August. I was diagnosed with osteopenia.

There is a great range of difference between osteopenia just over the cutoff for normal and osteopenia just below the cutoff for osteoporosis. In that we don't know what you were 2 or 5 or 15 years ago, a urinary NTX might be helpful to delineate the amount of bone loss you are currently experiencing.

All I have been able to find out in relation to the results 	is the bone loss is "moderate". I am having no menopausal symptoms and do not know whether I should begin 	hormone replacement therapy.

If you get regular periods and have no menopausal symptoms, then your aren't menopausal. Perimenopausal might be a better term. Birth control pills, recently shown to have no increased risk of breast cancer, may be a viable option.

When I consulted with my doctor, I expressed concern about 	breast cancer because I have cystic breasts.

No relationship has conclusivley been shown between cystic breasts (a subjective diagnosis in many) and breast cancer.

He told me that if I got cancer I would either live or die, 	but I did not want to get osteoporosis. He gave me a bag full of Premarin and told me to come back in a year.

If you get regular periods and are not menopausal, I'm not sure why one would be taking Premarin. If hormones are indicated, oral contraceptives, as noted above, might be more appropriate.

I did not start taking the hormones because I don't know 	what to do. How fast do the bones lose bone mass?

Depends upon the person. There are many medical conditions that may accelerate it as well as certain drug therapies that can predispose to it.

Would I possibly be a candidate for an osteoporosis drug 	since I am premenopausal and still have regular periods? If so, what drugs are available.

It appears that with certain inconsistencies in the history and treatment recommendations, a visit to an osteoporosis expert might be a good idea to delineate your possiblities as a perimenopausal patient.

Although I am 52 yrs old and pre-menopausal, a Dexa scan 	revealed osteopenia in my hip and low density in my spine. I've been placed on 5 mg. Fosamax and Arthrotec for 	occasional back pain in my hip and leg. My gyn. says that although my periods are irregular, I'm still producing 	more estrogen than could be gotten from HRT. My question is, at what point would HRT benefit me more than Fosamax 	, if at all?

Approximately 82% of women will be able to build bone with ERT/HRT but it is difficult to quantify how much good your estrogen is doing. A urinary NTX can be done to evaluate current bone loss to see if these changes may be, in part, due to recent bone loss as opposed to long term lower levels.

How bad is a reading of -.83 (spine) and -1.23 (hip) compared 	with women in my age group?

The interpretation is as follows: 0 to -1.00 is normal; -1.01 to -2.5 is osteopenia; less than -2.5 is osteoporosis of varying degrees. The spine is normal and the "hip" is "early" osteopenia. This may have been present for many years and may not, as noted above, represent recent loss. By the way, did you mean "in your age group" to mean that this is what the bone density result said? If so, the interpretation is different. The standard deviations noted above are for comparisons to 20-30 year olds (this is standard).

Harvey S. Marchbein, M.D. FACOG, FACS
 Great Neck, New York

Questions answered by Harvey Marchbein, MD