Birth Achieved After Effective Ovarian Stimulation Combined With Dexamethasone in a Patient With Resistant Ovary Syndrome: A Case Report and Review of the Literature

Background: Resistant ovary syndrome (ROS) was a rare endocrine disorder and there have been few reports of live births. As the ovarian resistance to FSH leading the immature oocytes, some researchers reported few live births after in vitro maturation (IVM) of oocytes, but it didn’t work in all ROS patients. Case presentation: A 30-year-old woman was diagnosed as ROS. GnRH analogue triptorelin acetat was used to administer downregulation, combining with corticosteroid dexamethasone (administered orally at 0.75mg three times daily) from the beginning of the downregulation to the day of oocyte collection. After 28 days of downregulation, gonadotropin (Gonal-f 225 IU and HMG 150 IU per day at rst) was given for hyperstimulation. On the 11th day of gonadotropin administration, 10000 IU of hCG was given. 36h later, oocytes were retrieved and followed by IVF procedure. Two months later, the frozen embryos were thawed and transferred. 8 metaphase II oocytes were retrieved and 3 embryos were developed, in which 1 embryo was transplanted after thawed. the β-hCG value in serum was 246.7 mIU/ ml. The patient got pregnant and gave a live birth at the 35 th week of pregnancy by Caesarean section. Conclusion This is the rst report about treatment ROS patient with ovarian stimulation combined with dexamethasone. In some cases of ROS, high doses of exogenous gonadotropins in combination with immunosuppressive therapy could be an effective approach in patients with ROS.


Introduction
Resistant ovary syndrome (ROS) is a rare endocrine disorder. Its concept was rstly proposed by Moraes-Ruehsen and Seegar Jones at 1967 (de Moraes-Ruehsen & Jones, 1967). They found that some cases of premature ovarian failure (POF) patients had milder symptoms and were not sensitive to gonadotropin, referred to as the resistant ovary syndrome (Jones & De Moraes-Ruehsen, 1969), which is characterized by amenorrhea, normal sex characteristics and follicle number. Furthermore, the ovary of ROS patient is not sensitive to high dose of exogenous gonadotropin. To date, the level of antimuellerian hormone (AMH) is included in the diagnostic criteria of ROS (Rogenhofer et al., 2015). Although the syndrome of ROS is well de ned, slow progress has been made in the treatment of ROS. At present, pregnancies obtained with self-oocytes are mainly achieved through hormone therapy (Amos, 1985 Twigg, Wallman, & McElduff, 1996). In this paper, we report a case of a patient diagnosed with ROS, who achieved clinical pregnancy, after treatment with high-dose gonadotropin and dexamethasone. This case report offers hints on a potential therapeutic for ROS.

Case Presentation
Patient history Patient Chen was a 30-year-old woman with BMI of 22.5, who was hospitalized due to secondary amenorrhea and infertility. Having been married for 10 years, she gave birth to a baby girl in 2009. Before coming to the center, the patient had undergone assisted reproductive technology (ART) in another hospital and failed to conceive, the detailed medical records of which was unavailable. Examination of her basic endocrine conditions (Table 1) indicated that the FSH value was higher than normal level, while the AMH concentration remained normal. Ultrasound scanning indicated that the uterine volume was relatively small (4.0cm*3.9cm*3.3cm). Sinus follicles more than 10 antral follicle were observed in both ovaries. Blood tests and genetic analysis excluded lupus erythematosus, multiglandular insu ciency, diabetes and myasthenia gravis, and chromosomal abnormalities (Fragile X syndrome, Turner syndrome, and Swyer syndrome). The patient has a karyotype of 46, XX.
According to the 5th semen analysis standard of world health organization, the husband's sperm concentration and motility were in the normal range, sperm acrosomal enzyme activity was normal. The study was conducted in accordance with the ethical guidelines of the institution concerned and with the informed consent of the patient. AMH, ng/mL (N: 2.1 -6.5) 6,29 6.14 T, nmol/L (N: 0.7 -3.1) 1.  During the whole period of down-regulation and controlled ovarian hyperstimulation the patient was orally administered dexamethasoneat 0.75mg daily. One embryo was thawed at day 20 (14 CII) and transplanted. Serum value of β-hCG was 246.7 mIU/mL at 13th day after the transfer, and vaginal ultrasonography showed clinical pregnancy 28 days after. The pregnancy evolved without complications until the 35th weeks, when the patient had oligohydramnios and gave birth to a baby girl by Caesarean section. The fetus weight 2200 g and was in good health.

Discussion And Conclusion
In this paper, we reported the clinical pregnancy treatment of one ROS patient. The rst ovarian hyperstimulation cycle inducted little ovarian response. Prior to the second cycle, we detected the presence of Ig-FSHR in the peripheral blood of the patients. Then we started the second cycle of ovarian hyperstimulation, while using of the immunosuppressant dexamethasone in the process of down-regulation and hyperstimulation, so as to reduce the FSHR antibody level in peripheral blood. The patient nally obtained 8 mature oocytes and frozen 3 embryos. Two months later, one embryo was thawed and transferred, nally the patient got clinical pregnancy and live birth.
Infertility is a huge problem for people of reproductive age with ROS, and the chances of having children with their own oocytes are unpredictable. The treatments of ROS has been under exploration. In previous cases of successful pregnancy, treatments were mainly conducted through hormone replacement therapy, controlled ovarian hyperstimulation, and IVM (Table 3). In early cases, different hormone replacement therapies were often used to restore normal menstruation (Fraser et al., 1986;Koninckx & Brosens, 1977;Mori et al., 1985;Starup & Pedersen, 1978;Sung et al., 2012;Tolino et al., 1984;Twigg et al., 1996). Later, it was found that patients with secondary ROS could obtain pregnancy through periodic estrogen administration (Jequier, 1990). For hormone therapy of ROS, estradiol, clomiphene, high-dose hMG and estradiol were commonly used (Mori et al., 1985). However, ROS showed signi cant individual differences.
Some cases of ROS could even recover spontaneously (Mueller et al., 2003), while other ROS had amenorrhea in general, but could get pregnant through hormone therapy more than once (Aslam et al., 2004). Therefore, the treatment of ROS is also according to the severity of the disease.
Some researchers considered that the different basic FSH levels can evaluate the degrees of ovarian follicle resistance to FSH more accurately than the follicle numbers (Huang et al., 2017). In views of our opinion, although the grading of ROS according to FSH levels can preliminarily determine the severity of ROS, it is not rigorous, because there were only 6 cases in this report, and the case reported by Galvao also proved that (Galvao et al., 2018) patient with normal FSH level could showed obvious resistance to gonadotropin stimulation. So, we considered that the FSH level can only re ect the follicular reactivity to ovulation drugs from one side, which can only be used for reference in the selection of treatment plan.
In . The authors found that gonadotropin resistance has the same immune mechanism as myasthenia gravis, and they con rmed that the serum of this patient contained a substance similar to gamma globulin, which inhibited the speci c binding of FSH to the receptor in vitro, this could be the reason of the ovary's non-response to gonadotropin stimulation. In 2004, Chiauzzi VA found that in their study, all the ROS patients had circulating immune complex in the serum, which might block the binding of FSH to its receptor(V. A. Chiauzzi et al., 2004).
Although there were evidences that ROS was highly linked to autoimmune disorder, few cases have been reported in which Ig-FSHR antibody activity was detected or corresponding immunotherapy was given in patients with ROS. In 2015, Rogenhofer described a ROS patient getting pregnancy through controlling stimulate ovulation. In their results, resistance to HMG positive signals were detected in the sera, so they chose recombinant follicle element of beta and high purity HMG for ovarian stimulation scheme and got a good ending, this was a good case for symptomatic treatment on the basis of cause. (Rogenhofer et al., 2015) In this paper, we detected Ig-FSHR antibody activity in patient's serum. Using standard Long GnRH agonist scheme, with large dose of gonadotropin, combining with immunosuppressive dexamethasone, the patient eventually got pregnancy. We provided possible hints in ROS treatment.
In general, ROS is closely related to autoimmunity, so we should identify the cause and then targeted treatment be carried out, which may greatly increase the success rate of ROS patients. For some patients with abnormal immunity of ROS, it can be an effective method to treat with large dose of gonadotropin drugs in combination with immunosuppressive agents.

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The authors declare that they have no competing of interest.

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Huiying Li was responsible for drafting the manuscript. Tianli Chang helped to diagnosis, treatment, literature research and manuscript writing. Hongbei Mu and Qiaojuan Mei helped to write the part of the manuscript and storage of data. Wenpei Xiang contributed to diagnosis, treatment plan and guideline of this study and manuscript revising. All authors read and approved the nal manuscript.