Endometriosis in women undergoing ovarian tissue transplantation due to spontaneous or induced premature menopause

Recently, Lotz et al. [1] reported the results of a retrospective study carried out on 17 women with premature menopause (spontaneous or induced) who had undergone ovarian tissue transplantation to restore their fertility, and were diagnosed with endometriosis during laparoscopic transplantation. The authors were interested in determining how endometriotic lesions after cytotoxic treatment and premature menopause might be explained, and whether endometriosis affects pregnancy rates. During surgery, it was found that twelve women had stage I endometriosis and five stage II endometriosis according to the rASRM classification; endometriosis foci were completely removed and ovarian tissue was transplanted into the pelvic peritoneum. Of the 17 women with endometriosis, 4 women were reported to have dysmenorrhea complaints, but none of the women reported general pelvic pain or dyspareunia. Prior to transplantation, four women who had taken hormone replacement therapy, four oral contraceptives and two tamoxifen. Following ovarian transplantation, pregnancy rate was 41.2% and the live birth rate was 35.3%. Pregnancy occurred in three cases after spontaneous conception, in four women after a natural cycle IVF/ICSI. The investigators concluded that there is an under-researched association between endometriosis in women entering premature or early menopause either after gonadotoxic treatment or due to primary ovarian insufficiency, recommending that specialists need to be aware of this condition as more and more women will use cryopreserved ovarian tissue transplant as an option to fulfill their desire to have children.

The present study analysed data of ovarian tissue transplantation used to restore fertility in women who had experienced premature menopause (spontaneous or due to gonadotoxic treatment). Khattak et al. [2] have stated that the technique of freezing ovarian tissue for subsequent transplantation has evolved over the last 20 years, with a pooled pregnancy rate of 37% (95% CI: 32–43%) and a live birth rate of 28% (95% CI: 24–34%) [2]. In the present commented study, of a total of 82 women, those who had endometriosis (n=17) were selected and then data evaluated. Personally I think this is an interesting research study idea.

Endometriosis is an enigmatic disease and when it occurs in women during the menopausal transition, it involves complex mechanisms. It is still unclear whether this represents a recurrence or continuation of a previous disease or a de novo condition [3].

Two patients had taken tamoxifen for 5-7 years before ovarian tissue transplantation and at the time of surgery for transplantation they were diagnosed with endometriosis. Tamoxifen, a selective estrogen receptor modulator, is an antagonist in breast cells yet it has an agonist in the uterus, which maybe the cause of endometriosis. Exacerbation of endometriosis due to tamoxifen has been previously addressed by Rose et al. [4], who reported the case of a 41-year-old woman with a history of endometriosis who was diagnosed with breast carcinoma and then treated with tamoxifen. Additionally, some women take hormone therapy, which can trigger the onset of endometriosis, as reported by Zanello et al. [5] in a literature review on hormonal replacement therapy in menopausal women with a history of endometriosis.

The present commented study found that the pregnancy rate in women with endometriosis who underwent ovarian tissue transplantation was 41.2% and the live birth rate was 35.3%. Contrary to this, lower rates of pregnancy (37%) and live births (28%) were found in a meta-analysis of Khattak et al. [2] regarding the results of ovarian tissue transplantation. It seems that the pregnancy rate in women with endometriosis who undergo ovarian tissue transplantation could be higher than that of normal women. Despite this, a large cohort study of women in their reproductive age found that the risk of infertility was increased two-fold in women with endometriosis as compared to women without [6].

In the present study [1], all 17 women had endometriosis stage I/II and visible lesions which were removed during laparoscopic ovarian tissue transplantation, so that it is suspected that the pregnancy rate of women with endometriosis is in fact higher than those without the disease. The data of the present commented study are strengthened by the results of the meta-analysis of two randomized controlled trials (n = 444) showing that laparoscopic ablation or resection of minimal and mild endometriosis increased ongoing pregnancy and live birth rates when compared to diagnostic laparoscopy [7]. This however, is not at all true. To highlight this, Dietl et al. [8] reported the first pregnancy and live birth achieved after thawed and refrozen ovarian tissue transplantation in a woman treated with chemotherapy who later subsequenty had surgery for endometriosis. Due to extensive pelvic endometriosis, ovarian tissue had to be frozen twice. Chemotherapy and endometriosis compromise ovarian reserve and fertility by several mechanisms; hence, this is the reason why primarily treating endometriosis becomes an important issue. From the above situation, the idea arises that the thawed tissue may then not be transplanted immediately and must be refrozen until the next attempt after the endometriosis has been treated [8].

In conclusion, researchers need to carry out further research, with a larger sample size, in order to answer some clinical questions and better assess the association between endometriosis and premature menopause in women who have received gonadotoxic treatment.

Hendy Hendarto, MD, PhD
PERMI-Indonesian Menopause Society
Department of Obstetrics and Gynecology
Faculty of Medicine, Universitas Airlangga,
Dr. Soetomo General Academic Hospital Surabaya, Indonesia

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References

1. Lotz L, Dietl A, Hoffmann I, et al. Endometriosis in women undergoing ovarian tissue transplantation due to premature menopause after gonadotoxic treatment or spontaneous premature ovarian failure. Acta Obstet Gynecol Scand. 2022;101(7):771–778.
   https://pubmed.ncbi.nlm.nih.gov/35514095/
2. Khattak H, Malhas R, Craciunas L, et al. Fresh and cryopreserved ovarian tissue transplantation for preserving reproductive and endocrine function: a systematic review and individual patient data meta-analysis. Hum Reprod Update. 2022;28(3):400-416.
   https://pubmed.ncbi.nlm.nih.gov/35199164/
3. Secosan C, Balulescu L, Brasoveanu S, et al. Endometriosis in Menopause—Renewed Attention on a Controversial Disease. Diagnostics (Basel). 2020;10(3):134.
   https://pubmed.ncbi.nlm.nih.gov/32121424/
4. Rose PG, Alvarez B, Maclennan GT. Exacerbation of endometriosis as a result of premenopausal tamoxifen exposure. Am J Obstet Gynecol. 2000;183(2):507-508.
   https://pubmed.ncbi.nlm.nih.gov/10942499/
5. Zanello M, Borghese G, Manzara F, et al. Hormonal Replacement Therapy in Menopausal Women with History of Endometriosis: A Review of Literature. Medicina (Kaunas). 2019;55(8):477.
   https://pubmed.ncbi.nlm.nih.gov/31416164/
6. Prescott J, Farland LV, Tobias DK, et al. A prospective cohort study of endometriosis and subsequent risk of infertility. Hum Reprod. 2016;31(7):1475– 82.
   https://pubmed.ncbi.nlm.nih.gov/27141041/
7. Jacobson TZ, Duffy JM, Barlow D, Farquhar C, Koninckx PR, Olive D. Laparoscopic surgery for subfertility associated with endometriosis. Cochrane Database Syst. Rev. 2010;CD001398.
   https://pubmed.ncbi.nlm.nih.gov/20091519/
8. Dietl AK, Dittrich R, Hoffmann I, et al. Does it make sense to refreeze ovarian tissue after unexpected occurrence of endometriosis when transplanting the tissue? J Ovarian Res. 2022;15(1):53.
   https://pubmed.ncbi.nlm.nih.gov/35513873/

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