A Severe Case of Recurrent External Endometriosis in An Ovariectomized Young Woman

This is a case of a 35-year-old ovariectomized woman with recurrent external endometriosis. During 15 years she has undergone 3 laparotomies, excisions of 159 recurrent abdominal wall endometriotic lesions and 12 vulvar, bilateral labia majora and pubis enodmetriotic lesions. Letrozole (7.5 mg/daily) treatment provided some relief of acute pain.


Introduction
Endometriosis is the growth of layers of tissues outside the uterus which is normally present inside the uterus. Mostly it occurs on the ovaries, fallopian tubes, and tissue around the uterus and ovaries This is a case of a 35-year-old ovariectomized woman with recurrent external endometriosis. This is the first case of extremely aggressive external endometriosis occurring in a reproductive-age.

Case Report
This is the case of a 35-year-old G1P1 with severe, recurrent endometriosis. 17 years ago she had initial abdominal surgery in which a right oophorectomy was performed due to a ruptured right ovarian cyst. Since then, she has undergone three abdominal surgeries for bilateral endometriomas and adenomyosis with a total hysterectomy, bilateral salpingo-oophorectomy and adhesiolysis. Between 2002 and 2007 her weight soared from 60 to 95 kg. In 2012 a rate of serum antimullerian hormone (AMH) was 0.3 ng/ml, whereas fluctuated substantly higher serum estradiol levels above the laboratory referent value (55 pg/ml) were monitored between 2007 and 2012. Values of the gonadotropic hormones were higher or in the above border of referent values: LH (52-73 mIU/ml) and FSH (70-127 mIU/ml). Levels of progesterone, prolactin and other hormones, including thyroid hormones were within referent values.
Finally, in 2007, she was ovariectomised. Hormonal profile monitoring presented high levels of serum estradiol, and due to relapses with severe pain we added letrozole orally 2.5 mg/daily to her regimen of danazole 800 mg daily. As this provided some relief of acute pain which was associated with the onset of relapses, in 2012 by patient's own decision the dose was titrated up to 7.5 mg/day, which proved relatively beneficial in terms of symptoms and substantially decreased estradiol concentrations ( Figure 1). However, this treatment was associated with side effects such as increased body mass, headaches, pain in the extremities, dizziness, insomnia, memory impairment.
An attempt to decrease letrozole dose (5 mg/day) was accompanied by a severe external endometriosis relapse both on the anterior abdominal wall and the labia majora. This called for an increased letrozole dose (7.5 mg) and surgical treatment.
Most striking, however, are the 159 surgical procedures for recurrent abdominal wall endometriotic lesions and twelve surgeries for recurrent vulvar and bilateral labia majora and pubis (mons) enodmetriotic lesions (Figures 2-4). She had failed treatment with GnRH-agonists, testosterone derivatives, danazol, dienogest, norethisterone, NSAIDs and antibiotics. Therefore, she was subjected to recurrent multiple procedures in order to remove endometric lesion relapses.
We observed wound dehiscence with secondary healing or nonhealing wound formation in cases of suturing. In some cases purulent lesion discharge from the wound was noted which was successfully healed after excision and removal of endometriotic lesions and wound debridement with severe disfigurement ( Figure 5). Endometriotic tissue was confirmed only in 16 of 159 samples from abdominal wall lesions, whereas in most cases histological examination was not performed or severe purulent inflammation was registered. During the next LT (2007) she experienced adhesiolysis, total hysterectomy and right ovaryectomy due to adenomyosis, an endometriotic right cyst and severe adhesions described as a frozen pelvis. Thus, in her thirties, our patient was ovariectomised. This was followed by 159 surgical procedures for recurrent abdominal wall endometriotic lesions and 12 surgeries for recurrent vulvar and bilateral labia majora and pubis (mons) enodmetriotic lesions in the ensuing 6 years.
Relapses were accompanied by severe localized pain. Rapid relief of symptoms was possible by the concurrent surgical removal of disparate endometriotic lesions.
All traditional conservative treatment options failed and due to persistent high concentrations of serum estradiol levels, letrozole was prescribed. Only high doses of this medication were successful in preventing relapses with decreased serum estradiol concentrations.
Several factors may be a cause of external endometriosis in individuals with severe external endometriosis relapses, such as the shift of a major source of circulating estradiol from the ovary to the adipose tissue [1] and the aromatization of androstendione by human adipose tissue stromal cells [2,3]. Therefore aromatase inhibitors were applied to treat patients with endometriosis. This in a case report of external endometriosis relapses after initial ovarian endometriosis in ovariectomized woman [4] and a series of four cases in premenopausal patients [5]. There are several studies that have shown the benefit of aromatase inhibitors in this kind of severe refractory endometriosis [4][5][6], although the role of aromatase in the development of endometriosis and its subsequent beneficial impact is under debate [7,8].
In our patient substantially decreased serum concentration of AMH, accompanied with increased serum estradiol and gonadotropins (FSH and LH) levels are features of postmenopausal hormonal profile. A decreased serum estradiol concentration after letrozole treatment is associated with interruption of extraovarian pathway of estradiol production.
In 2004, a similar case was published [4]. A young ovariectomized woman who presented with severe, recurrent endometriosis and an analogous letrozole treatment was initiated. Both her pelvic pain and dyspareunia significantly decreased after a three-month letrozole treatment. Decreased serum estradiol levels were observed and remained low until the end of treatment. Then, a beneficial impact of letrozole in the reduction of pain and urinary symptoms was shown in two patients with bladder endometriosis [6][7][8].
Letrozole has also been shown to impact refractory endometriosisrelated chronic pelvic pain, as presented in four premenopausal patients [5]. Aromatase inhibitors have been examined in post-menopausal women as well [9].
Recently, in a phase-two, open-label, nonrandomized proof-ofconcept study [10], a combination of letrozole and norethindrone acetate markedly reduced laparoscopically-visible and histologically-confirmed endometriosis in ten reproductive-age patients and significantly improved pain relief in nine out of ten women with endometriosis and chronic pelvic pain who had previously not responded to currently available treatment.

Discussion
To our knowledge the first case of extremely aggressive external endometriosis occurring in a reproductive-age, ovariectomized woman was presented. She experienced 175 repeat surgical procedures and pain relief was achieved only by a daily triple dose of letrozole.

Briefly, our patient initially (1998) experienced LT for right
In all of these cases, aromatase inhibitors were found to be beneficial in recommended therapeutic doses. In our patient, pain relief and decreased estradiol concentrations were seen only after high doses of letrozole treatment, likely due to the strong de-activation of the androgen-to-estrogen conversion pathway [3,11]. However, when the recommended daily dose of letrozole was tripled up to 7.5 mg per day, there were undesirable side effects [12].

Conclusion
This case of extremely aggressive external endometriosis occurring in a reproductive-age, ovariectomized woman represents a novel observation of hitherto unknown relevance. She obtained pain relief only from high doses of letrozole treatment, but produced undesirable side effects affecting her general health. We are fully aware of the undesirable side effects of this medication and it is not to be recommend as a treatment of choice for recurrent endometriosis.
More research needs to be done regarding this type of recurrent external endometriosis and the appropriate treatment options for this condition.