LATEST ON UTERINE TRANSPLANT- A DISAPPOINTING OUTCOME FOR THE FIRST UTERINE TRANSPLANT IN U.S.

The recent achievement of successful uterine transplant by Professor Brannstrom from Europe opens up a new excitement in the field of reproductive medicine.  This new surgical technology gives hope to women with uterine factor infertility, to conceive. Currently, the European team had reported five babies born to mothers with transplanted uteruses

On February 25th, 2016, the Cleveland Clinic in United States, similarly reported its successful uterine transplant, using a uterus from deceased donor.  However, the recipient developed complications within a week.  This had led to removal of the transplanted uterus on March 8th.  The preliminary report showed that the complication was due to infection that compromised the blood supply to the newly transplanted uterus.  The US team is actively looking into improving the protocols to reduce the risk of this complication in the future.

MRI GUIDED FOCUSED ULTRASOUND (MRIGFUS)- A NOVEL APPROACH TO THE TREATMENT OF UTERINE FIBROID?

Uterine fibroid is one of the commonest benign tumor amongst women.  It is present in 30%  of premenopausal women and is the main indication for hysterectomy.  Currently, there is no effective medical treatment available.  The uterine artery ablation has been offered as alternatives to surgical treatment (hysterectomy) but its clinical application is limited.

The MRI guided focused ultrasound is a minimally invasive fibroid treatment that uses a tightly focused ultrasound waves to deliver heat that instantaneously destroys fibroid tissue.  It is performed as an outpatient procedure with sedation.  The fibroid location is identified using T2-weighted MR imaging followed by a pretreatment planning and application of multiple therapeutic sonications to a temperature of at least 65 degree Celsius.  The heat generated basically ablates the fibroid tissue. The whole procedure takes about two to three hours.  The recovery time of about one to three days appears promising as a viable alternative to the current surgical option.

There are many reports of the experience with this treatment modality.  These reports were not from a high quality study design and occasionally sponsored by industry that are prone to bias and confounding.

There is only one randomized, placebo-controlled trial (PROMISe) to date, that assess the effectiveness of MRIgFUS therapy.  This is a high quality study and has a post treatment follow-up period of 2 years duration.  The result shows there is no diffence between MRIgFUS and placebo group, in terms of symptom improvement and quality of life at 4 to 12 weeks post procedure.  However, about a third (30%) of all women who had MRIgFUS therapy opted for hysterectomy by 2 years post treatment.

In summary, the MRIgFUS treatment for uterine seems promising and avoids the need for surgery.  Currently, the available results suggest its role as a temporary alternative treatment prior to the decision for hysterectomy, at best.

Reference

PROMISe trial (Pilot Randomized trial of MRIgFUS for symptomatic fibroid) trial. Fert Steril 2016

Alternative therapies in management of leiomyomas. Fert Steril 2014

Clinical improvement and shrinkage of uterine fibroids after thermal ablation by magnetic resonance-guided focused ultrasound surgery. Ultrasound Obstet Gynecol 2007.

Clinical outcomes of focused ultrasound surgery for the treatment of uterine fibroids.  Fert Steril 2006

 

 

 

RECURRENCE OF ENDOMETRIOSIS – HOW TO PREVENT IT

Endometriosis is a common, benign gynecological disorder and a leading cause of disability in women of reproductive age, responsible for dysmenorrhea, pelvic pain and subfertility.  It is a debilitating and costly disease. Surgery is the treatment of choice for its management since the efficacy of medical treatment alone is often inadequate or of limited efficacy.  Surgical excision of lesions (conservative surgery) has been shown to both improve pain and enhance fertility. This is preferred over radical surgery because most women with endometriosis are of reproductive age.

The recurrence rate

Recent reviews had estimated the recurrence rate of endometriosis to be 21.5% at 2 years and 40-50% at 5 years (Guo SW 2009), which is more frequent than previously believed.  It seems that the recurrence rate for pain or dysmenorrhea is higher than that for the clinical recurrence as defined by presence of ovarian endometrioma on pelvic ultrasound scan.  These recurrences, which lead to repeat surgeries can further reduce fertility, exacerbate pain and complications of operation, which in turn affects quality of life, and increases social costs.

How recurrences happen?

There are two main explanations leading to the recurrence of endometriosis, namely re-growth of residue lesion and de novo lesion formation.

Vignali et al. observed that during a repeat surgery, most endometriosis recurrence occurred at the same area.  Similar observation was found in cases of ovarian endometrioma, where majority (88.7%) of the recurrences was from the previously treated ovary (Guo SW 2009). Conservative surgery is sometimes insufficient to remove these lesions completely, allowing it to re-develop after operation.  The de novo endometriosis lesion occurs via the monthly retrograde menstrual blood flow into the abdominal cavity, allowing the endometrial tissue to implant.

Prevention of Recurrence

Pain symptoms

The pain symptoms of endometriosis include non-cyclical pelvic pain (chronic pelvic pain), painful menses and intercourse. The use of oral contraceptives (OC) for a period of six month or more is found to be effective in reducing endometriosis associated pain symptom recurrence.   The continuous OC regime has an advantage over the cyclical OCs, with lower recurrence and earlier benefits (Seracchioli 2010; Vlahos 2013).  Medication should be given for at least 18-24 months as the recurrence occur rapidly when medication is stopped.

 

Ovarian endometriosis (endometrioma)

Postoperative OC conveys a protective effect against recurrence.  Again, the continuous regime has an edge over the cyclical OC regime.  This benefit is conferred as long as the woman is on OC treatment but vanished rapidly upon discontinuation (Kaori K 2015).

Recommendations

All women with endometriosis, following a conservative surgery (for pain symptoms or endometrioma), should be on medication (continuous OC) as long as possible until she is ready to conceive (Dunselman GA 2014). This will effectively reduce endometriosis recurrence and need for repeat surgery, which carries its own complications.

References

  1. Dunselman GA et al., Hum Reprod 2014
  2. Guo SW. Hum Reprod Update 2009
  3. Kaori K et al., Fert Steril 2015
  4. Seracchioli R et al., Fert Steril 2010
  5. Vlahos N et al., Fert Steril 2013
  6. Vignali M et al., J Minimal Invasive Gynecol 2005

CERVICAL MUCUS MONITORING- A SIMPLE WAY TO ENHANCE PREGNANCY CHANCE

The fertile window period is defined as the 6-day period ending on the day of ovulation (Brosens 2006). Intercourse is mostly likely to result in pregnancy when it occurs within this period.  The peak fecundability was observed when intercourse occured within 2 days prior to ovulation (Wilcox 1995).  It is desirable to predict the fertile window period and ovulation, to optimize conception rate but can be challenging with the available methods.  Amongst the methods available, include calendar method, basal body temperature (BBT), urinary LH detection, cervical mucus monitor, urinary estrogen metabolites and transvaginal ultrasound scan for follicle tracking.

Cervical mucus monitoring (CMM) is a prospective and inexpensive method to detect fertile window.  It was found to be as good as or better than BBT or urinary LH monitoring to predict the day-specific probabilities of conception (Bigelow 2004).  The cervical mucus is observed at the vulvar for its appearance and sensation.  Type 1 and 2 are typically present at the beginning of menstrual cycle.  They are associated with a dry (type 1) or damp (type 2) sensations at the vulva.  Type 3 is typically thick, creamy and whitish or yellowish mucus with damp sensation.  The type 4 cervical mucus is transparent, stretchy or elastic (raw egg white) with wet or slippery sensation.  Intercourse at this period is associated with a high conception rate.

Hoeker et al., observed that CMM when applied consistently resulted in increased fecundability. It is more effective for timing of intercourse than the calendar method, as it allows identification of onset and duration of fertile window to be determined prospectively.  It reduces the overall time to pregnancy.

CMM is a free, self-directed method used to detect fertile window prospectively.  When applied consistently, it reduces the interval to conception and enhances fecundity.

Note:

Fecundity : Ability to conceive or to produce offspring

Reference:

  1. Bigelow JL et al., Human Reprod 2004
  2. Brosens I et al., Sex Reprod Menopause 2006
  3. Evans-Hoeker E et al., Fert Steril 2013
  4. Wilcox AJ BMJ 1995

WHAT IS ENDOMETRIAL HYPERPLASIA?

I had prolonged uterine bleeding.  My gynecologist performed an endometrial curettage (DD&C) and confirmed findings of endometrial hyperplasia.

 

Endometrial hyperplasia

Endometrial hyperplasia is a condition due to abnormal thickening of the endometrium (womb lining) because of unopposed estrogen hormone stimulation.  The commonest etiology of this condition is anovulation (failure to ovulate).

Women usually present with prolonged menstrual bleeding, which can be mild spotting to heavy menstrual flow.  These symptoms can cause personal distress and inconvenience to anemia (pallor) due to chronic blood loss.

 

Making the diagnosis

The pelvic ultrasound usually shows a thickened endometrium characterized by an echogenic endometrium.  Curettage of the endometrium provides opportunity to remove the abnormal endometrium as well as tissue assessment.  A hysteroscopy examination of the uterine cavity provides further opportunity to exclude polyps or sinister uterine growth.

The diagnosis of endometrial hyperplasia depends on the histopathology results.  The endometrium examination may reveal findings of a simple or complex hyperplasia (types of thickening based on cellular layering). This is further classified depending on the presence of atypia (abnormality of cell structure).  The final diagnosis will appear as a simple or complex hyperplasia with or without atypia. However, for purpose of uniformity, WHO (2014) has recommended the use of Endometrial Hyperplasia without atypia and Atypical Hyperplasia to describe these pathologies.

 

The concern: Endometrial hyperplasia and endometrial (womb) cancer

The presence of endometrial hyperplasia is a precursor to endometrial (womb) cancer.  However, the risk of malignant transformation is less than 5% over 20 years for endometrial hyperplasia without atypia.

On the other hand, the risk of developing endometrial cancer is highest in atypical hyperplasia. The reported cumulative risk of cancer in 4 years is 8%, which increases to 12.4 after 9 years and to 27.5% after 19 years (Lacey JV 2010).  About 43% of this atypical hyperplasia has also been associated with a concomitant endometrium cancer at time of hysterectomy (Trimble 2006).

 

Treatment options

In view of low risk of endometrial cancer in women who have endometrial hyperplasia without atypia, an option of observation alone with follow-up biopsies can be considered. The majority of these cases regress spontaneous during follow- up.  However, treatment with progestogens has a higher disease regression rate over observation alone.  Progestogen treatment is indicated in women who fail to regress following observation alone and in symptomatic women with abnormal uterine bleeding.

Progestogen can be administered orally or by injections.  The other alternative is the use of medicated IUCD. The recommended duration of treatment is 6 months and this is followed by a endometrial biopsy confirm endometrial regression.  Two negative biopsies over six months interval are required to complete the treatment.  Any vaginal bleeding should be assessed and a relapse excluded.

Surgery is rarely indicated unless the women opted for it and do not wants medical treatment.  Other indications for surgery include failure of endometrial regression following medical treatment, persistent uterine bleeding and relapse after a completed progestogen treatment.  A hysterectomy (complete removal of the womb) is the recommended surgical option.

The treatment of endometrial hyperplasia with atypia is hysterectomy.  This is due to the high likelihood of progression to endometrial cancer. For women who prefer to keep the uterus, medical treatment in the forms of progestogen or medicated IUD can be used for women who want to preserve their uterus until a later date.

 

REFERENCE

Lacey JV et al., J Clin. Oncol 2010

RCOG Greentop guideline 2016

Trimble CL et al., Cancer  2006

 

 

 

ENDOMETRIOSIS AND RISK OF OVARIAN CANCER- Can endometriosis predispose to ovarian cancer?

Endometriosis is a common gynecological disorder.  It affects up to 10% of women in the reproductive age.  The common presentations of endometriosis are menstrual or pelvic pain, ovarian cyst and difficulty to conceive.  There has been report of malignant (cancerous) transformation of endometriosis.

Ovarian cancer is the one of the deadliest gynecology cancer as most women present at later stage of the disease.  The current treatment includes pelvic clearance, removing as much tumor as possible while the residue tissues are treated with chemotherapy.  However, the 5 years survival rate for late stage ovarian cancer remains low.  This creates anxiety and concerns amongst health professionals as well as women suffering from endometriosis.

 

Endometriosis, a precursor to ovarian cancer

There are strong evidences to support that endometriosis predisposed women to the risk of developing ovarian cancer (Nezhat 2014).  The endometriosis tissue exhibits ability to ‘travel’ (spread) to distant organ.  It does not confine itself to the female reproductive organ but can metastasize to other organs in the body.  It attaches and invades the target organ and subsequent lead to end organ damage. The endometriosis itself manifests recurrence, uncontrolled cell proliferations and growth driven by estrogen hormone.

Recently, based on molecular genetic studies, ovarian cancer can be classified into two categories, namely types I and II.  The type I tumors develop gradually, less aggressive and usually confined to the ovary at diagnosis.  They comprise approximately 25% of all ovarian cancer and have better prognosis.  These type II ovarian cancers are endometrioid, clear cells and low- grade serous subtypes.

The type II tumors are more aggressive, rapid growing and demonstrate high- grade malignancy.  There is no known precursor lesions associated with type II ovarian cancers.

They seems to arise from the fimbrial epithelium and highly unstable chromosomally (Kurman 2011).

 

How high is the risk?

The exact likelihood for a malignant transformation in women with endometriosis is unknown.  It has been found that there is a 2-3 folds risk of women with endometriosis to develop a clear cell or endometrioid ovarian cancers, compared to women without endometriosis.  These tumors are from the Type I category.  The estimated relative risk (RR) are 3.59 and 1.98 respectively (Guo 2015).

With the lifetime risk of ovarian cancer estimated at 1.4% and approximately 25% of all ovarian cancers are Type I origin (clear cell and endometrioid subtypes), the lifetime risk would be 0.34% in the general population. For women with endometriosis, the odds ratio of developing ovarian cancer is about 1.5 compared to the general female population.  An odds ratio of 1.5 means that a woman with endometriosis has a life-time risk of developing an ovarian cancer of about 1.5% instead of 1% (Pearce 2012).

The risk factors associate with malignant transformation include, women with long- standing history of endometriosis, endometriosis diagnosed at an early age, endometriosis associated with infertility, ovarian endometrioma and atypical endometriosis.

 

Final message

Endometriosis, a seemingly benign gynecological condition has shown to be associated with ovarian cancer.  However, most women with endometriosis do not develop ovarian cancer as the risk of malignant transformation remains low.  The manifest tumors are also less aggressive.

 

Notes:

Odd s ratio is the odds that an outcome (ovarian cancer) will occur given a particular exposure (endometriosis), compared to the odds of the outcome occurring in the absence of that exposure (without endometriosis).

Relative risk describes the probability of developing a disease (ovarian cancer) in the exposed (endometriosis) to the non- exposed group (non-endometriosis)

 

Reference:

  1. Pearce CL et al. Lancet Oncology 2011.
  2. Guo SW et al., Fert Steril 2015
  3. Kurman RJ et al., Hum Pathol 2011
  4. Nezhat FR et al., Int J Gynecol Cancer 2014
  5. Nezhat F et al., Fert Steril 2014

FERTILITY DECLINE WITH INCREASING MATERNAL AGE

Fertility is defined as the capacity to produce a child.  It is generally observed that 80% of couple will conceive in the first six months of attempting pregnancy (Gnoth 2003).  The monthly fecundity (the probability of pregnancy per month) is greatest in the first 3 months. The fertility rate is reduced by half among women in their late 30s compared to women in their early 20s (Dunson DB 2004).   This proved that age alone is the most important predictor of fertility.

Studies has shown that the pregnancy rate was 74% in women younger than 31 years compared to 62% for women ages 31-35 years and 54% for women older than 34 years of age.  Even with state of art IVF technology, the livebirth rate for younger than 35years was 41.5%, compared to at  12.1% at 40-44 years old.  The fertility rate decreases with increasing maternal age.

 

Reasons for a reduced fertility rate

The numbers of eggs in the woman’s ovaries are finite. It decreases naturally and progressively with age.  The total number of eggs is approximately 1 million at birth, 500,000 at puberty and is reduced to 1000 at menopause. The availability of eggs is one of the essential process of conception.  Fecundity defined as ability to conceive, decrease gradually but significantly at age of 32, then rapidlyly after age of 37.

Besides this natural loss, there is also a deterioration of egg quality as demonstrated by increasing FSH and decreasing AMH.  The risks of other disorders associated with ageing such as fibroid, tubal disease and endocrine condition may adversely affect the woman’s fertility.

 

Increase miscarriage rate in elderly mother  

Early pregnancy loss has also showed an increasing trend with advance maternal age.  This is partly due to increase in abnormal chromosome (aneuploidy), especially autosome trisomies.  The incidence of spontaneous miscarriage is 10% in women younger than 30 years; 20% in 41-42 years and 36.6% in older than 42 years

 

Conclusion

Women should be aware of the effect of age on fertility, should they choose to delay starting a family.  Given the decline in fertility, increase in pregnancy loss and pregnancy risk with aging, women older than 35 years should seek early medical attention if they fail to conceive after 6 months of attempting pregnancy.  For women who are older than 40 years, immediate evaluation and treatment are warranted.

 

Reference

Dunson DB et al., Am J Obstet Gynecol 2004

Gnoth C et al., Human Reproduction 2003