Myomectomy in infertile patients Prof. Abbas Aflatoonian 14 th International Congress on Obstetrics and Gynecology October 14-17, Tehran - Iran

Subjects Myoma,Description and types Effect on fertility and IVF/ICSI outcome Myoma and gene expression Myomectomy, When? Whom? Conclusions

Myomas appear to arise from a mutation in a single myometrial cell Regulated factor : estrogen, progesterone, local growth factors Myomas are the most common benign tumors of the female genital tract and occur in about 20-50% of women They are associated with many gynecological problems including heavy menstrual bleeding and infertility. Yoshino O, et al. Human Reproduction 2010;25(10):2475–9.

Types of fibroids 1.Submucos (SM): Fibroid distorting the uterine cavity: Type 0: pedunculated without intramural extension Type I: Sessile with intramural extension <50% Type II: Sessile with intramural extension >50% 2. Intramural (IM): Fibroid not distorting the cavity with <50% protrusion into serosal surface 3. Subserosal (SS): >50% protrudes out of the serosal surface The European Society of Hysteroscopy, 1993

Myoma and infertility Myomas are present in approximately 5%– 10% of women with infertility Fibroids and are estimated to be the sole cause of infertility in less than 3% of cases Depending on size, number and location in the uterus, myomas have been implicated in both recurrent pregnancy loss and infertility Farquhar C. BMJ 2009;16:338.

The outcomes of women with any location of fibroid, clinical pregnancy, implantation, and ongoing pregnancy/live birth were all significantly lower in women with myomas than in control subjects The spontaneous abortion rate was significantly greater in women with fibroids Pritts et al, Fertile Steril Apr;91(4):

The women with SM fibroids, compared with infertile women without fibroids, demonstrated a significantly lower clinical pregnancy rate, implantation rate, and ongoing pregnancy/live birth rate and a significantly higher spontaneous abortion rate. No difference was seen in rate of preterm delivery. Women with no cavitary involvement had a significantly decreased implantation rate and ongoing pregnancy/live birth rate as well as an increased spontaneous abortion rate compared with nonfibroid control subjects. No significance was seen in preterm delivery rates Pritts et al, Fertile Steril Apr;91(4):

When women with SS fibroids were examined in comparison with women without fibroids, no difference was observed for any outcome measure. In contrast, women with IM fibroids produced significantly lower clinical pregnancy rates, implantation rates, and ongoing pregnancy/live birth rates and significantly higher spontaneous abortion rates. No difference was seen in the rate of preterm delivery Pritts et al, Fertile Steril Apr;91(4):

Submucosal fibroids had the strongest association with lower ongoing pregnancy rates, through decreased implantation. Cumulative pregnancy rates appeared slightly lower in patients with intramural fibroids (36.9% vs 41.1%) Patients with intramural fibroids also experienced more miscarriages, 20.4% vs 12.9%. There was no conclusive evidence that intramural or subserosal fibroids adversely affect fecundity.

Fertility outcomes are decreased in women with submucosal fibroids, and removal seems to confer benefit. Subserosal fibroids do not affect fertility outcomes, and removal does not confer benefit. Intramural fibroids appear to decrease fertility, but the results of therapy are unclear. More high-quality studies need to be directed toward the value of myomectomy for intramural fibroids, focusing on issues such as size, number, and proximity to the endometrium.

Myoma and IVF/ICSI outcome

Live birth as an outcome showed a statistically significant 21% relative reduction in women with non-cavity-distorting intramural fibroids compared with women without fibroids Clinical pregnancy as an outcome showed a statistically significant 15% reduction in women with non-cavity-distorting intramural fibroids, following IVF treatment Sunkara et al, Hum Reprod, 2010 Feb;25(2):

Result showed statistically non-significant 13% reduction in IR in women with non-cavity- distorting intramural fibroids Miscarriage as an outcome showed a statistically non-significant 24% relative increase in miscarriage rate in women with non-cavity- distorting intramural fibroids, following IVF treatment Sunkara et al, Hum Reprod, 2010 Feb;25(2):

In asymptomatic patients selected for IVF, small fibroids with a diameter < 50 mm and not encroaching the endometrial cavity do not impact on the rate of success of the procedure. This result should not, however, be used to conclude that all intramural or subserosal lesions are unremarkable. In fact, current available evidence indicates that at least some lesions may be deleterious.

Results suggest that fibroids not encroaching upon the uterine cavity may not have a strong adverse effect on IVF/ICSI outcomes. A subgroup of IM fibroids with SFD>2.85 cm was found to have significantly lower DR than matched nonfibroid controls. Type 3 IM fibroids did not portend a poorer response to IVF/ICSI compared with matched controls. Small IM fibroids with an SFD≤2.85 cm do not negatively affect the main IVF outcomes including CPR, MR, and DR.

Myoma and gene expression The homeobox (HOX) genes encode transcription factors that guide embryologic development as well as regulate d with each menstrual cycle. HOXA10 expression is necessary for endometrial receptivity. In the mid-secretory phase at the time of implantation, HOXA10 messenger RNA(mRNA) expression is up-regulated in both endometrial glandular and stromal cells in women.

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Result showed statistically significantly decreased HOXA-10 and HOXA-11 transcript levels in infertile patients compared to controls. There was no significant decrease in HOXA-10 protein levels between these groups. A significantly higher level of HOXA-11 protein was reported in the endometria of infertile patients compared to controls. HOXA-10 and HOXA-11 proteins were localized in the nuclei of the endometrial stromal cells. Immunohistochemical analyses did not reveal differences between amounts of HOXA-10 and HOXA-11 protein levels in infertility and control groups. The results suggest that HOXA-10 and HOXA-11 gene expression in the endometrium during the implantation window may not be altered in patients with idiopathic infertility.

The study has identified lower expression of HOXA11, LIF and BTEB1 in women with myoma that may result in inadequate preparation of a receptive endometrium. HOXA11, LIF and BTEB1 mRNA are not the only molecules responsible for successful implantation.

Myomectomy Hysteroscopic myomectomy is choice for SM myoma IM myomectomy may perform via laparoscopy or laparotomy Note: Correct repair in the bed of myoma is essential The best time for myomectomy is 3-6 months before desire pregnancy Repeated myomectomy is difficult and may lead to unwanted hystrectomy For SS myoma mostly no surgery unless for very huge myomas

If fibroid removal is beneficial, myomectomy subjects would be expected to have higher pregnancy rates and lower abortion rates than those with fibroids in place. In those with SM fibroids, clinical pregnancy rate is indeed higher in the myomectomy group, but the ongoing pregnancy/live birth rate fails to reach statistical significance. The spontaneous abortion rate appears unchanged. In women with IM fibroids, no significant differences are seen. Pritts et al, Fertile Steril Apr;91(4):

Conclusions Myoma may interfere with fertility specially SM and IM myoma Treatment perform via surgery, hystroscopy, laparoscopy or laparotomy Repair of bed of myoma is crucial and the best time is 3-6 months before desire pregnancy Molecular and genetic problem due to myoma may increase Indication for myoma in future