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 insufficiency, 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.
Table 1 Hormonal profile
|
2019-3-14
|
2019-4-12
|
FSH, IU/L (N early follicular phase: 2.5 - 10.2)
|
42.37
|
40.8
|
LH, IU/L (N early follicular phase: 1.9 - 12.5)
|
15.13
|
11.49
|
E2, pg/mL (N early follicular phase: 11 - 69)
|
15
|
11
|
AMH, ng/mL (N: 2.1 - 6.5)
|
6,29
|
6.14
|
T, nmol/L (N: 0.7 - 3.1)
|
1.8
|
--
|
P, ng/mL (N early follicular phase: 0.38 - 2.28)
|
0.15
|
--
|
PRL, mIU/L (N: 72 - 511)
|
408.94
|
--
|
FT3, pmol/L (N: 4 - 10)
|
4.92
|
--
|
FT4 pmol/L (N: 9 - 25)
|
18.39
|
--
|
TSH, mIU/L (N: 0.3 - 5.0)
|
3.01
|
--
|
AFC (2 - 12 mm) (N: 12 - 24)
|
> 20
|
28
|
Abbreviations: N, normal ranges; FSH, follicle-stimulating hormone; LH, luteinizing hormone; E2, Estradiol; AMH, anti-mullerian hormone; T, testosterone; P, progesterone; PRL, prolactin; FT3, free triiodothyronine; FT4, free thyroxine; TSH, thyroid stimulating hormone; AFC, antral follicle count.
Controlled Ovarian Hyperstimulation and IVF
After administrated on March 4, 2019, the patient received two cycles of ovarian hyperstimulation (Table 2). The first one (May 19, 2019) was started with 3.75 mg of GnRH analogue triptorelin acetate injection (FERRING, Switzerland), and gonadotropin (300IU/d, 15d) at cycle day 30, which was abandoned due to follicular dysplasia. Then the second cycle started at July 6, 2019, when the patient was first given a 3.75 mg of triptorelin acetate injection for down-regulation on the second day of menstruation. Controlled ovarian hyperstimulation was initiated at day 30 with daily subcutaneous injections of gonadotropin recombinant FSH (Gonal-f Merck Serono, Darmstadt, Germany) 225 IU/d and HMG 150 IU/d for 3 days and then daily Gonal-f 225 IU/d, HMG 225 IU/d and Luveris (Merck Serono, Darmstadt, Germany)75 IU/d for 7 days. During the hyperstimulation period, the folliculometry with ultrasonography, and estradiol, luteinizing hormone, follicle-stimulating hormone and progesterone were measured to monitor follicular maturation. Then 10,000 IU human chorionic gonadotropin (HCG) was administered (lizho pharmaceuticals, China) with s.c. injection. 36h later ultrasound guided transvaginal follicular aspiration was performed under the negative pressure of 110 mmHg (14.7 kpa) using a single lumen aspiration needle (Cook; William Cook Australia Pty Ltd, Australia). A total of 8 Metaphase II (MII) oocytes were collected. After in vitro fertilization 3 embryos were vitrified and cryopreserved, and the remaining embryos were discarded.
During the whole period of down-regulation and controlled ovarian hyperstimulation the patient was orally administered dexamethasoneat 0.75mg daily.
Table 2 Cycle characteristics and results in patient with resistant ovary syndrome
Cycle No.
|
Protocol
|
Hormon
|
Total gonadotropin
(IU)
|
Days of stimulation
|
Serum E2 on oocyte retrieval day (pg/mL)
|
Numbers of follicles (>14mm)
|
MII
|
D3 embryo
|
The Result
|
1
|
Long GnRH agonist
|
Triptorelin Acetate Injection
|
3000
|
14
|
--
|
Follicular dysplasia
|
0
|
0
|
Cycle the cancel
|
2
|
Long GnRH agonist
|
Triptorelin Acetate Injection
|
4800
|
10
|
1973
|
8
|
8
|
3
|
Pregnant
|
Abbreviations: GnRH, gonadotropin-releasing hormone; MII, Metaphase II oocytes; D3, the third day.
Frozen-thawed embryo transfer and follow-up
2 months after the second ART cycle, hormone replacement cycle for Endometrial preparation was started at day 3 of menstrual cycle, consisting of 5 days with 4 mg and then 5 days with 6 mg of estradiol valerate tabletes (Bayer, Germany). Endometrial thickness was 7 mm at day 13, and 9 mm at day 16 after additional 3 days with 8 mg of estradiol valerate. The serum E2 at day 16 was 346 pg/mL. Progesterone (0.05 ng/Ml) and human chorionic gonadotropin (HCG, 10000 IU) were injected at the night of day 16.
Progesterone luteal support with vaginal tablets containing 40 mg of progesterone (Utrogestan, Besins, Paris, France) daily was started on day 17, and continued until the day of the hCG test and, if pregnant, until 10 weeks of pregnancy.
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.
Table 3 Cases of ROS received pregnancy through different treatments
Author
|
Patient No.
|
Age at
intake
|
Type of
infertility
|
BMI
(kg/m2)
|
Basal
AFC
|
AMH
(μg/L)
|
Ovarian histology
|
E2
|
FSH
|
Ig-FSHR
|
Infertility treatments before pregnant
|
Medication/hormonal pretreatment
|
Result
|
Amos, W. L., Jr. (1985)(Amos, 1985)
|
1
|
41
|
Secondary
|
NA
|
NA
|
NA
|
NA
|
NA
|
88.4 IU/L
|
NA
|
HRT
|
Estrogens, medroxyprogesterone acetate
|
Liveborn
|
Jequier, A. M. (1990)(Jequier, 1990)
|
2
|
28
|
Secondary*
|
NA
|
NA
|
NA
|
NA
|
31-52 pmol/L
|
125 U/L
|
NA
|
HRT
|
4 cycles (Mestranol + Norethisterone)
|
Liveborn
|
3
|
30
|
Secondary*
|
NA
|
NA
|
NA
|
normal ovarian stroma and follicles
|
76 pmol/L
|
range seen in
postmenopausal women
|
NA
|
HRT
|
Mestranol + Norethisterone
|
Normal pregnancy
|
Nawroth, F. and R. Sudik (1999)(Nawroth & Sudik, 1999)
|
4
|
32
|
Secondary
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
HRT
|
2 mg estradiol valerate and 2 mg estradiol valerate/0.15 mg levonorgestrel
|
Liveborn
|
Mueller, A., et al. (2003)(Mueller et al., 2003)
|
5
|
26
|
Primary
|
NA
|
NA
|
NA
|
normal density of
follicles
|
NA
|
70 IU/L
|
NA
|
HRT
|
2 mg estradiol valerate and 0.5 mg norgestrel per day administered sequentially
|
Liveborn
|
Aslam, M. F., et al. (2004)(Aslam et al., 2004)
|
6
|
19
|
Secondary
|
NA
|
NA
|
NA
|
NA
|
NA
|
133.9 U/L
|
NA
|
HRT
|
2 mg estradiol valerate and 0.5 mg norgestrel
|
Twice liveborn
|
7
|
24
|
Secondary
|
27
|
NA
|
NA
|
NA
|
NA
|
Higher than normal
|
NA
|
HRT
|
estradiol valerate and norgestrel
|
Normal pregnancy
|
Zielinska, D. and I. Rzepka-Gorska (2011)(Zielinska & Rzepka-Gorska, 2011)
|
8
|
31
|
Secondary
|
NA
|
NA
|
NA
|
NA
|
18.1 pg/ml
|
58.2 IU/mL
|
NA
|
HRT
|
(spontaneous recovery of ovarian function after HRT)
|
liveborn
|
Ezeh, U. I. O. and A. J. Breeson (1995)(Ezeh & Breeson, 1995)
|
9
|
32
|
22
|
NA
|
NA
|
NA
|
NA
|
39 pmol/L
|
95-115 IU/L
|
NA
|
Ovarian Hyperstimulation
|
eight ampoules of
menotrophin (Pergonal) daily for 14 days
|
Liveborn
|
Rogenhofer, N., et al. (2015)(Rogenhofer et al., 2015)
|
10
|
26
|
Secondary
|
22
|
15
|
2.1
|
NA
|
28.7 pg/mL
|
50.8 U/mL
|
antibodies directed to hMG but not to recFSH
|
Controlled Ovarian Hyperstimulation and IVF
|
GnRH analogue
Narfarelin, recombinant follitropin beta, hMG
|
liveborn
|
Grynberg, M., et al. (2013)(Grynberg et al., 2013)
|
11
|
29
|
primary
|
normal
|
23 and 18
|
4.50 and 4.36
|
NA
|
<15
|
40.3 and 38.4 mIU/mL
|
NA
|
IVM
|
17ß-E2, hCG
|
liveborn
|
Li, Y., et al. (2016)(Y. Li et al., 2016)
|
12
|
33
|
Secondary*
|
NA
|
25
|
12.27
|
NA
|
260.57 pmol/l
|
41.99 IU/L
|
NA
|
IVM
|
estradiol valerate, hCG
|
liveborn
|
Galvao, A., et al. (2018)(Galvao et al., 2018)
|
13
|
29
|
primary
|
27.7
|
37
|
8.6
|
NA
|
NA
|
27.7 IU/L
|
NA
|
IVM
|
no
|
liveborn
|
14
|
36
|
primary
|
18.9
|
40
|
2.11
|
NA
|
NA
|
7.9 IU/L
|
NA
|
IVM
|
HP-hMG 150 IU/day for 5 days, hCG
|
liveborn
|
15
|
23
|
primary
|
24.8
|
50
|
2.88
|
NA
|
NA
|
49.1 IU/L
|
NA
|
IVM
|
17ß-E2, hCG
|
Twice liveborn
|
Abbreviations: BMI, body mass index; AFC, antral follicle count; AMH, anti-mullerian hormone; HRT, Hormone Replacement Therapy; IVM, in vitro maturation; ART, assisted reproductive technologies; recFSH, ; FSHR, ; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; hMG, human menopausal gonadotropin; HP-hMG, highly purified human menopausal gonadotropin; 17ß-E2, estradiol-17ß; NA, not applicable.
*One live birth after spontaneous birth