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UPA after IVF failure

Ulipristal acetate (UPA) for fibroids–IVF outcomes following treatment with UPA after IVF failure:
series of 2 case reports

Asha Kiran Hospital, Nursing home, and IVF Centre, Pune, Maharashtra, India

INTRODUCTION

The failure to become pregnant after assisted reproductive techniques depends upon but is not limited
to the ability of the embryo to implant and attach itself to the healthy endometrium. One of the commonest reasons why this can be hampered is the presence of uterine fibroids, particularly sub-mucous and intra-mural ones. The distance between the fibroid and the endometrial cavity is the main
factor which decides the impact on implantation and successful pregnancy outcome. Along with the
distance from cavity, the size and number are also important. Even after conception, a pregnancy with
a uterine fibroid is considered as a high-risk pregnancy.

There is an increased rate of complications such as miscarriage, preterm birth, degeneration of
fibroid, etc.

The factors predisposing to uterine fibroids include age, African ancestry, obesity and nulliparity
. Although studies performed to date have extended our knowledge of fibroid pathology, their Etiology has not been fully elucidated. With an increasing population of sub-fertile and infertile
women, the incidence of fibroid is increasing manifold. They are often even seen as an incidental diagnosis in these group of women, who are routinely subjected to an ultrasound screening
before deciding the modality of treatment. Here, we report a case series of 2 women, with fibroids,
who were put on UPA prior to IVF. These women had at least one previous IVF failure.

Uterine fibroids are present in approximately 70% and 80% of 50-year-old white and black women,
respectively.

4 Common symptoms include heavy menstrual bleeding and subsequent anemia, pelvic pain, dysmenorrhea, decreased quality of life, and reproductive dysfunction.

The optimal treatment for patients with symptomatic uterine fibroids and pregnancy desire remains
unknown. It has been reported that myomectomy may improve fertility outcomes in women with
submucosal and intramural fibroids. Nevertheless, there is still insufficient evidence from randomized
controlled trials to establish the effect of myomectomy to improve fertility.

4 On the other hand, current evidence is still insufficient to establish whether radiologic procedures represent a valid treatment option for women with symptomatic fibroids who want to preserve their fertility

Alternative medical therapies have limitations and are not considered a valid fertility-preserving
treatment option. Uterine fibroid growth depends on the ovarian steroids estrogen and progesterone. Accordingly, oral progestin may promote fibroid growth and induce abnormal bleeding. Although the progestin-releasing intrauterine device would control heavy menstrual bleeding, it is hardly ever used in women with a deformed endometrial cavity by submucosal fibroids and also prevents pregnancy if used.

Therefore, the mode of management of fibroids in women who desire pregnancy depends on the size,
number and location of uterine fibroids. The mainstay of management remains the surgical approach
when indicated.

Further on, the results of studies conducted by Lai et al, Noor et al and Eze et al support the
need for treating uterine fibroids before planned pregnancy to minimize the risk of complications described
above.

6-8 There are convincing data that progesterone and its receptors increase the proliferation activity of
the cells in uterine leiomyomata, hence treatment with anti-progestins and progesterone receptor modulators seems to be reasonable 3,5.

Results of a successfully completed phase III clinical trials with the application of ulipristal acetate
(UPA) (first-in-class selective progesterone receptor modulator–SPRM) have been published recently.

UPA is a selective P receptor modulator (SPRM) that potently modulates P-receptor
activity with proapoptotic/antiproliferative effects on fibroid cells and with pharmacokinetic
properties supporting once-daily dosing. Two short-term (3 months) randomized clinical trials
showed that UPA effectively controls HMB and shrinks fibroids.9,10 After treatment cessation,
menstruation usually returns within 4-5 weeks, but fibroid volume reduction can be sustained for up
to 6 months.

Administration of 5 mg or 10 mg UPA daily has been shown to rapidly stop (within a week) excessive
uterine bleeding, reduce the volume of the three largest fibroids by -44.8% and -54.8% for UPA 5 mg and 10 mg, respectively. The effect on fibroid volume has been observed for up to 6 months after treatment cessation.

It is also important that UPA restores patient Quality of Life scores to the level of healthy women and in the majority of patients resume menstruation and ovulation within one month after treatment cessation.

When compared with the Gn-RH agonist (leuprolide acetate), UPA has controlled uterine bleeding faster and more consistently (7 days vs. 30 days), fibroid reduction  for up to 6 months has been smaller for Gn-RH a (-16.5%) and UPA has shown a superior safety profile as estradiol levels are maintained in the mid-follicular range.

The presented results on the application of UPA in the medical treatment of symptomatic uterine
fibroids are very promising and gynecologists are given a new treatment option.

Ulipristal treatment has not shown any adverse effect on the quality of embryos in the morphological assessment during the ICSI procedure. Pregnancy does not induce changes in fibroid size following earlier treatment with ulipristal acetate.

However, since UPA exerts mainly antiprogestogen effects on the endometrium, whether the ART
protocols have to be modified, need further studies.

Also, in the studies so far, it has been observed that the effect of UPA is best-seen up to 6 months
of cessation of the drug. Therefore, for women who require ART, it should be planned within this
time frame.

Although larger and randomized control studies are required to further reinforce the fact,
treatment of uterine fibroids is a promising treatment modality before planned pregnancy to improve
fertility, enhance ART results, and to minimize the risk of obstetric complications.
Below we report 2 cases of pre-IVF Ulipristal, where uterine fibroid shrinkage was seen enabling
ART without prior surgery for fibroids.

CASE REPORT

Case 1

A 31-year-old woman with primary infertility presented to us following one failed IVF cycle done
outside 1 year ago for unexplained causes. With us, the couple infertility work-up revealed normal
the study, except multiple uterine fibroids, which probably grew during the past 1 year when she did
not seek any treatment.

The couple was counseled regarding the impact of cavity distorting, as well as the peripheral
intra-mural fibroids. Both options were offered-laparohysteroscopic myomectomy and Ulipristal
Acetate for 3 months. Not wanting to undergo surgery, the couple chose to take the medical
management.
The woman was put on 5 mg daily dose of Ulipristal acetate for 12 weeks. A fibroid mapping was
repeated after 12 weeks of UPA therapy. The comparison of fibroids pre and post UPA are tabulated
in Table 2.
To enable a better comparison of the pre and post UPA effects on fibroids, a fibroid mapping, and a
sketch was done. The sagittal uterine sketch of the fibroids, pre, and post-UPA is shown in Figure
1. After the UPA therapy cessation, she was taken for an IVF in the immediate cycle. 8 oocytes were
retrieved, and 6 fertilized – 3 Grade A, 2 Grade B and 1 Grade C. A fresh embryo transfer was done
of the 2 Grade A embryos.
The beta hCG value on Day 16 was 1600 mIU/mL. A single viable intra-uterine gestational pregnancy
was documented at 6 weeks, which was followed upto 9 weeks, and is ongoing till submission of this
paper.

Case 2 :

A 26-year-old lady with primary infertility. She had 2 failed IVF cycles-one done outside, and one
with us. There was no obvious cause of infertility except multiple fibroid uterus, of which 2
fibroids were indenting the endometrial cavity. The woman was firmly against surgery – we had tried
to convince her prior to our 1st IVF cycle too.

The fibroid mapping, case 2, has been tabulated in
Table 3. Having refused surgery strongly, before going ahead with the 2nd IVF cycle, we offered her
UPA with an aim to shrink the fibroids, and improve the distorted cavity. She was also counseled
that the isthmic fibroid, which abutted against the endometrial cavity, may cause difficulty while
performing the embryo transfer.

Not wanting to undergo surgery, the couple chose to take 5 mg daily dose of Ulipristal acetate for
12 weeks. A fibroid mapping was repeated after 12 weeks of UPA therapy. The comparison of fibroids
pre and post UPA are tabulated in Table 4.

The sagittal uterine sketch of the fibroids, pre and post UPA, for case 2, is shown in Figure 2. We
had frozen embryos from her previous IVF cycle, and a FET was performed after a good lining was
formed. Her beta hCG was positive on day 16, and a TVS at 6 weeks showed a single viable intra
uterine gestation, which has been carried till 14 weeks, when this article

In infertile women, appropriate evaluation and classification of fibroids, particularly those
involving or suspected to be involving the endometrial cavity is essential. Our findings support
UPA as an efficient and safe treatment to reduce the size of uterine fibroids. However, its
shrinkage effect involves also the small myometrial myomas that distort uterine morphology, and the
proven restoration of uterine anatomy maximizes the chances of a successful IVF.

Further studies are needed to clarify

• The role of UPA in IVF candidates
• Whether such a medical management could avoid surgical procedures
• Whether there are specific cases of uterine leiomyomatosis (localization, dimension, number of
fibroids) that would be eligible to the sole medical treatment with UPA
• Any detrimental effect of UPA on endometrial phase hampering IVF response.

was submitted. The pregnancy is ongoing and uneventful so far.

CONCLUSION

Although there is currently insufficient evidence to recommend medical treatment in the management of fibroids, UPA seems to be a novel and promising option, especially for infertile women who refuse to undergo surgery inspite of the fibroids distorting the cavity, and for those with fibroids who shall undergo IVF.
It has shown future promise in our small case series, however further, well designed RCTs are needed. Although no pregnancy-related complications or teratogenic effects have been reported to date, further series are required in order to establish the safety of ulipristal acetate as a treatment of symptomatic fibroids prior to IVF and pregnancy.

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