Medical management of adenomyosis: current and future therapies

The current issue of Journal of Fertility and Sterility has focused exclusively on etiology, pathophysiology, and medical and surgical treatment of adenomyosis. Adenomyosis has long been the source of controversy and its only with the recent advent of Transvaginal sonography (TVS) and MRI that its etiology and pathophysiology been better understood.

Adenomyosis is a uterine pathology in which the endometrial glands and stroma invaginate within the uterine myometrium. This ectopic endometrium induces hypertrophy and hyperplasia of the myometrium resulting in the typical ‘globular” enlargement of the uterus.

It is also now known that endometriosis and adenomyosis are two different phenotypes of the disorder characterized by impaired cellular response to ovarian hormone. This concept has to lead to the use of common treatment modalities for both the diseases.

Transvaginal sonography (TVS) and MRI are now the gold standards for diagnosing adenomyosis. Adenomyosis requires a lifelong treatment plan that depends upon patient’s age, desire for children and symptoms. Medical management is the treatment of choice for women who want to preserve fertility, while hysterectomy is preferable in older women who have completed the childbearing.

No new drug has been developed in recent years for the treatment of adenomyosis although many new drugs are under development and undergoing clinical trials.  

Medical management includes minimally invasive procedures as well as medication to treat the symptoms.

Minimally invasive surgical procedures help preserve fertility as well as reduce the pain and abnormal uterine bleeding (AUB) and include endometrial ablation and resection, laparoscopic as well as open excision of adenomyosis and MRI-guided focused ultrasound. They are offered to patients who have not responded to medical drug treatments. 

The medical treatment is mainly aimed at easing the symptoms, improving quality of life and promote fertility. The rationale behind using these drugs is based on the pathophysiology of the disease which includes aberrant response to the ovarian hormone, inflammation, and impaired apoptosis.

http://journals.sagepub.com/doi/full/10.5301/je.5000261

The class of drugs includes:

Current Medical Treatments: 

GnRH agonist: These group of drugs cause a downregulation of GnRH activity and induce a reversible state of medical menopause. Goserelin, leuprolide, and nafarelin are commonly used in clinical practice before fertility treatments to improve the chances of pregnancy in infertile women with adenomyosis.

Progestins: Drugs such as danazol, norethindrone acetate (NETA), Levonorgestrel-releasing intrauterine system (LNG-IUS), and Dienogest are mainly used because of anti-inflammatory properties to relieve pain and reduce the amount of abnormal uterine bleeding.

The Levonorgestrel-releasing intrauterine system (LNG-IUS) has been found extremely effective in reducing menorrhagia and decrease the uterine volume over a period of 12 months use.

Combined oral contraceptives (COC): They are effectively used to reduce pain and control bleeding with the additional advantage of long-term use with minimal side effects.

Future Medical treatments:

Selective estrogen receptor modulators (SERMs)

Aromatase inhibitors (AIs)

Selective progesterone receptor modulators (SPRMs)

Valproic acid

Anti-platelets therapy

NSAIDs

Thus, the medical treatment of adenomyosis comprises many current and future drugs. No double-blind, RCTs have yet been conducted in the management of adenomyosis and the drugs are solely used based on results of observational studies.

Abstract

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Value of hormonal treatment in endometrial hyperplasia debated— News from ACOG Annual Clinical and Scientific Meeting 2016.

The John I. Brewer Memorial Lecture on Day 2 of the Annual Clinical and Scientific meeting, ACOG  2016 considered the role of hormones in treatment of Endometrial Hyperplasia vs the common surgery of Hysterectomy.

Debaters were David E. Cohn, MD, professor in the Department of Obstetrics and Gynecology and director of the Division of Gynecologic Oncology at The Ohio State University College of Medicine, and Amanda Nickles Fader, MD, associate professor and director, The Kelly Gynecologic Oncology Service and Johns Hopkins Hospital in Baltimore. They all agreed that when treatment is tailored according to patient need both forms can be beneficial.

Dr. Cohn opined that in patients who are fit for surgery and have completed the family the most effective and definitive way of preventing the transition into endometrial cancer is hysterectomy. He cited the 2006 prospective cohort study in which out of 289 women with atypical endometrial hyperplasia on biopsy or curettage,42.6 percent had endometrial cancer at hysterectomy within 12 weeks of sampling. He also said that hormonal treatment has to be continued for an indefinite period of time vs hysterectomy which is a one-step procedure with much higher success rates.

He also referred to a meta-analysis of 34 observational studies in which progestins were used to treat atypical endometrial hyperplasia. The statistical analysis showed that while 86% of women saw regression, 3.6% of women had ovarian cancer and 1.9% had advanced endometrial cancer.

He further quoted “That’s sobering news about the potential for bad outcomes with progestins.”

He acknowledged the committee opinion from 2015 that says “Progestin treatment was an unproven but commonly used alternative to hysterectomy, but optimal doses and duration of treatment need to be defined and post-hormonal surveillance and frequency is yet to be determined. It is also not determined whether it should be continuous or cyclical. And also lacks the optimal clinical as well as histological measures of response.”

He concluded by seconding the ACOG committee opinion of lots of unanswered questions regarding the use of progestins therapy.

The second debater Dr. Fader argued in favor of progestins therapy and stressed that the surgical option is chosen more out of fear than by evidence, nonetheless ample evidence exists in support of hormonal treatment.

As times have changed in last 15 years and in contemporary times, a number of organ-sparing treatments have become a reality. She further said “Almost all endometrial hyperplasia is sensitive to hormonal treatment and most — including atypical hyperplasia — regresses or remains unchanged without therapy and doesn’t progress to cancer.”

She presented evidence in the form of results of 150 retrospective studies and 12 prospective, in which progestin treatment brings about atypical hyperplasia regression in 75 to 95 percent of cases. 

Additional review of 4 large studies also showed that progestins were associated with regression of hyperplasia due to unopposed estrogens in 90% of patients.

Dr. Fader also said that with 40% of endometrial hyperplasia patients are obese or want to retain fertility, making hormonal treatment a valid choice for them. Endometrial hyperplasia is a public health problem due to increasing demographics of obesity and endogenous estrogen production, with many of the women younger than 45 years of age, which increases the need of exploring life style modifications and treatment beyond surgery a viable option.

Both the debaters agreed upon the impact of obesity on endometrial hyperplasia and the Dr.Cohn pointed out that early data on  bariatric surgery is promising in converting abnormal endometrium into normal endometrium without surgery. 

References:

http://www.acog.org/-/media/Committee-Opinions/Committee-on-Gynecologic-Practice/co631.pdf?dmc=1&ts=20150426T1515499455

http://www.acogdailynews.com/role-of-hormones-in-endometrial-hyperplasia-debated/

Progestins in Endometrial Cancer ------ It’s all about the targeted mode of drug delivery!

Endometrial cancer is the sixth most common cancer in women worldwide (fourteenth most common cancer overall), with 320,000 new cases diagnosed in 2012.

In the United States, as with other developed countries, uterine cancer was the most common gynecologic malignancy, with over 50,000 new cases and almost 8600 deaths from the disease in each year.

The 5-year prevalence of women globally living with endometrial cancer is 46.8 per 100,000 (estimated from incidence and observed survival by cancer and age group).

 It is estimated that half million cases of endometrial cancer would be diagnosed worldwide by 2035.

Adenocarcinoma of the endometrium (lining of the uterus) is the most common histologic site and type of uterine cancer.

Endometrial hyperplasia is the precancerous condition that eventually will progress into endometrial cancer.
It is classified into four categories on the basis of histological appearance; the simple hyperplasia has only 1% chance of developing into cancer while complex hyperplasia with atypia has 25% chance of ending into malignancy.

The main risk factor for endometrial carcinoma is an excess of endogenous or exogenous estrogen without adequate opposition by a progestin (eg, postmenopausal estrogen therapy without a progestin). Other risk factors include tamoxifen therapy, obesity, and nulliparity.

The main symptom of endometrial cancer is irregular bleeding, and every patient with this symptom should be thoroughly investigated!

Once the diagnosis is made, the treatment could be medical or surgical depending on the histologic type, the patient age future desire for fertility and other risk factors!

In this systemic review and metaanalysis by Hashim  H.A et al published in October issue of  AJOG evaluated the therapeutic efficacy of levonorgestrel-releasing intrauterine system (LNG-IUS) with oral progestins for treatment of non-atypical endometrial hyperplasia (EH).

Seven RCTs were included amounting to a sample size of 766 women, (329 in the LNG-IUS group and 437 on oral progestin group).

All the women included in the study had simple or complex hyperplasia without atypia.

The oral progestin preparations used included medroxyprogesterone acetate (MPA), norethisterone acetate, and dydrogesterone.

Histological response was evaluated as the main outcome measure at follow-up pathologic examination at 3, 6, 12, and 24 months of treatment. The type of endometrium looked at was proliferative, secretory, atrophic, or inactive endometrial pattern.

A need for hysterectomy and the frequency of irregular bleeding were also analyzed as secondary outcome measure.

It was seen that LNG-IUS fared quite well as compared to oral progestin, the odds ratio at increased from 2.30 at 3 months to 7.46 at 24 months, with fewer patients being ended up in hysterectomy in the LNG-IUS group.

In fact another meta-analysis by Beining R.M et al showed a preventive effect of LNG-IUS on the rate of development of endometrial cancer.

There was no significant difference in rate of irregular bleeding between the two groups.
It was concluded that LNG-IUS could be safely offered to those women, who have atypical hyperplasia and who wish to retain the uterus.

LNG-IUS also has other advantage over oral progestins. Significantly higher dose of the drug could be delivered at the site of pathology without any systemic side effects.

A pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium has shown that LNG-IUS induces a number of immunological and biochemical changes in the uterine environment that could affect endometrial cancer (EC) risk and progression.

The limitations of review were most studies included had a short follow up of 1 year and didn’t include women with atypia. Studies doing longer follow up are needed before the full potential of LNG-IUS is exploited.

References:

1. http://www.ajog.org/article/S0002-9378%2815%2900267-7/abstract
2. http://www.cancer.gov/research/progress/snapshots/endometrial
3. http://www.uptodate.com/contents/endometrial-carcinoma-epidemiology-and-risk-factors
4. http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/endometrial-cancer-cancer-lining-womb-statistics
5. http://onlinelibrary.wiley.com/doi/10.1002/ijc.29229/abstract
6. http://www.sciencedirect.com/science/article/pii/S1047279707004905
7. Meta-Analysis of Intrauterine Device Use and Risk of Endometrial Cancer Beining, Robin M. et al. Annals of Epidemiology, Volume 18, Issue 6, 492 - 499