|Year : 2019 | Volume
| Issue : 1 | Page : 49-53
Influence of growth hormone supplementation in patients with thin endometrium undergoing frozen embryo transfer
Jun-Yi Yang1, He Li1, Nan Lu1, Lu Li1, Xiao-Xi Sun2
1 Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
2 Shanghai Ji Ai Genetics and IVF Institute; Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
|Date of Submission||02-Jan-2019|
|Date of Web Publication||11-Apr-2019|
Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital of Fudan University, 588 Fangxie Road, Shanghai 200011
Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital of Fudan University, 588 Fangxie Road, Shanghai 200011
Source of Support: None, Conflict of Interest: None
Objective: To evaluate the effect of recombinant human growth hormone (rhGH) supplementation during hormone-replacement therapy and frozen-thawed embryo transfer (FET) in patients with thin endometrium.
Methods: A retrospective research was conducted on 225 patients, who underwent artificial cycle FET in Shanghai, China, between January 2016 and November 2017. Data from 245 FET cycles were analyzed, of which 184 cycles received rhGH (GH group) and 61 did not (control group).
Results: Clinical pregnancy and implantation rates were significantly higher in the GH group than those in the control group (64.7% vs. 49.2%, P = 0.032; 44.8% vs. 32.8%, P = 0.019, respectively). After logistic regression analysis, rhGH was considered the only significant variable that influenced clinical pregnancy rate, increasing it by 1.89-fold. On the other hand, the presence of rhGH did not seem to affect the early pregnancy loss.
Conclusions: Our results indicated that simultaneous addition of rhGH could improve clinical outcomes of FET in patients with thin endometrium, particularly in patients between 30 and 34 years of age.
Keywords: Endometrial Receptivity; Frozen-Thawed Embryo Transfer; Growth Hormone; Thin Endometrium
|How to cite this article:|
Yang JY, Li H, Lu N, Li L, Sun XX. Influence of growth hormone supplementation in patients with thin endometrium undergoing frozen embryo transfer. Reprod Dev Med 2019;3:49-53
|How to cite this URL:|
Yang JY, Li H, Lu N, Li L, Sun XX. Influence of growth hormone supplementation in patients with thin endometrium undergoing frozen embryo transfer. Reprod Dev Med [serial online] 2019 [cited 2019 Apr 24];3:49-53. Available from: http://www.repdevmed.org/text.asp?2019/3/1/49/255983
| Introduction|| |
In the past few decades, assisted reproductive technology (ART) has made tremendous progress. Although the clinical pregnancy rate is gradually increasing, the results remain unsatisfactory. The European Society of Human Reproduction and Embryology had suggested in 2012 that only 33.8% of embryo transfer eventually leads to successful clinical pregnancy. Embryo implantation failure has been a major limiting factor in ART., The implantation process is complicated, requiring the apposition and invasion of the embryo and endometrium. At a specific stage of the menstrual cycle, a series of changes occur in the endometrium that prepares it for receiving the developing embryo in an optimal state. This ability is called endometrial receptivity, and the short and precise period is referred to as the window of implantation. Impaired uterine receptivity is one of the major reasons for implantation failure.
Endometrial thickness (EMT) is currently an important parameter for the evaluation of uterine receptivity. Thin endometrium implies that EMT is below the threshold at which pregnancy can be achieved. EMT < 7 mm has been reported to imply a lower chance of pregnancy. Because the threshold varies across different studies,,,, the criterion still lacks a consensus. Most scholars believe that, on the day of progesterone supplementation in hormone-replacement therapy, EMT < 8 mm may be considered as thin endometrium., Patients with thin endometrium may receive various adjuvant therapies to promote its growth and guarantee efficient conception;, however, the true benefit is actively debated.
Growth hormone (GH) is a peptide hormone secreted by the anterior pituitary gland. Apart from promoting the metabolism of our body, it also regulates the reproductive process via the GH receptor (GHR) or insulin-like growth factor (IGF). GH can improve oocyte quality, as suggested previously., Some reports have found GH to generate more oocytes and increase embryo retrieval. However, review of all the published data did not identify its effect on endometrial receptivity, especially due to the limited number of reports available.
The clinical outcome of fresh cycles of in vitro fertilization (IVF) may be affected by numerous factors. As a complementary therapy of IVF, frozen-thawed embryo transfer (FET) is considered safe and cost-effective. Besides maternal age and embryo quality, endometrial receptivity plays a crucial role in the implantation process of FET.
To investigate the influence of recombinant human GH (rhGH) on endometrial receptivity, the current study applied rhGH during the endometrial preparation for FET in patients with thin endometrium.
| Methods|| |
Study period and participants
This retrospective study investigated all patients, who underwent FET cycles between January 1, 2016, and November 31, 2017, in Shanghai, China. Inclusion criteria included age of 40 years or younger and receiving two blastocysts transferred. In addition, only the patients with EMT < 8 mm on the progesterone administration day were considered. All the included patients underwent surgical management of intrauterine adhesions through hysteroscopy before their FET cycles. Exclusion criteria included uterine malformations, severe endometriosis or adenomyosis, and contraindications for GH treatment such as tumor and diabetes mellitus. Preimplantation genetic screening or preimplantation genetic diagnosis and immune abnormalities were also excluded. No oocyte donor was included. Cycles with other adjuvant treatment including aspirin, sildenafil, and Vitamin E were excluded.
A total of 225 women, with 245 FET cycles, were included; 184 cycles had rhGH supplementation (GH group) and 61 cycles were free from rhGH and hence designated as a control group.
For endometrial preparation, a single intramuscular injection of gonadotropin-releasing hormone agonist (1.25 mg) was administered in the midluteal phase of the preceding menstrual cycle. Estradiol valerate, at a daily oral dose of 4 mg, was administered from the 2th or 3th day of this cycle. Besides, virginal estradiol 1 mg/d was added after menstruation. If the EMT remained < 8 mm after 2 weeks, we continued this regimen for another 7 days. Then, embryo transfer was commenced despite inadequate EMT. Patients received 40 mg progesterone twice a day, as intramuscular injection, to imitate the mid-cycle shift to secretory phase. After 5 days of progesterone administration, embryos were thawed and transferred. GH (4.5 IU every alternate day) was subcutaneously injected starting from the day of progesterone administration till the day of embryo transfer.
Blastocysts were graded according to the Gardner scoring system, including inner cell mass (A = numerous tightly packed cells, B = several and loosely packed cells, or C = very few cells) and trophectoderm (A = many cells organized in epithelium, B = several cells organized in loose epithelium, or C = few large cells). A good-quality embryo was defined as one ≥ BB (AA, AB, BA, and BB).
Data analysis and statistics
The primary outcome was clinical pregnancy rate. Transvaginal ultrasound was conducted 4 weeks after embryo transfer. Clinical pregnancy was determined by the presence of a gestational sac. Embryonic developmental arrest or spontaneous abortion at < 12 weeks of pregnancy was defined as early abortion. The data were analyzed by SPSS version 19.0 (SPSS Inc., Chicago, IL, USA) using logistic regression, two-sample t-tests, Chi-square test, or Fisher's exact test, as appropriate. Logistic regression was used to assess the independent contribution of individual confounding parameters on clinical outcomes such as age, body mass index (BMI), basal hormone levels, previous IVF attempts, and EMT. Effect of each variable was expressed as an odds ratio (OR) with associated 95% confidence interval; P < 0.05 was considered statistically significant.
Patient consent and ethical approval
Because all procedures and blood tests were performed following routine clinical protocols, we did not apply for specific ethics approval. However, retrospective analysis and reporting of data were approved by the Ethics Committee of Assisted Reproductive Medicine in Shanghai JiAi Genetics and IVF Institute (JIAI E2018-19).
| Results|| |
Overview of growth hormone and control groups
Among the included patients, there was no significant difference between the two groups with regard to BMI, age, duration and reasons of infertility, previous IVF attempts, and basal sex hormone level (including follicle-stimulating hormone [FSH], estrogen, and progesterone). Both groups showed similarity in the number of oocytes retrieved, available embryos, fertilization rate, and proportion of different controlled ovarian hyperstimulation and IVF/intracytoplasmic sperm injection cycles [Table 1]. No statistical difference was found in the estrogen and progesterone levels or EMT on the progesterone administration day and in the quality of blastocysts transferred in FET cycles [Table 1]. Despite the same number and similar grade of blastocysts transferred, 119 out of 184 cycles in the GH group attained clinical pregnancy (64.7%), which was quite higher than that in the control group (30 out of 61, 49.2%, P = 0.032) [Table 1]. In addition, the implantation rate was significantly higher in the GH group than that in the control group (44.8% vs. 32.8%, P = 0.019) [Table 1]. The presence of rhGH did not seem to affect the early pregnancy loss (17.7% vs. 10.0%, P = 0.41) [Table 1].
Univariate analysis using logistic regression
We calculated clinical pregnancy OR s for each variable individually. Only the presence of GH was found to be the significant predictor of clinical pregnancy probability. Maternal age, BMI, basal FSH, progesterone and estrogen levels, EMT, or previous IVF attempts did not influence the clinical pregnancy rates [Table 2].
Correlation between growth hormone treatment and maternal age
From subgroup analysis based on age, we found the clinical pregnancy rates to reduce with age in both groups. More importantly, the positive effect of rhGH was clearly dependent on the patient's age. Women aged between 31 and 34 years were 2.86 times more probable to achieve pregnancy in the GH group [Table 3]. However, rhGH supplementation might not alter the possibilities for those older than 35 or younger than 30 years of age.
| Discussion|| |
As is evident from our study, low-dose rhGH can significantly enhance clinical pregnancy and implantation rates in patients with thin endometrium, undergoing FET. Besides, the rate of early pregnancy loss was unaffected, thereby suggesting it as an effective and safe adjuvant.
Based on logistic analysis, we noted that GH supplementation was the only reliable predictor of clinical pregnancy rate. Other characteristics of the patient, including maternal age, BMI, EMT, and number of previous IVF attempts, did not have an independent effect on clinical pregnancy as per the current analysis. From subgroup analysis based on age, younger patients were found to have better possibilities for clinical pregnancy in both GH and control groups, although without any statistical significance. The age-dependent decline in fertility has been reported in several previous studies; however, it was not obvious from our study, probably due to the small sample size. The effect of rhGH was most apparent in women aged between 31 and 34 years, illustrating a clear age-dependence and implying that the above age interval may be the most appropriate for rhGH supplementation. We speculated that the age advantage in our younger patient group (age ≤ 30 years) could compensate for the lack of rhGH. While in the older patient group (age ≥ 35 years), GH was not able to improve their pregnancy outcome because fertility declines with age.
Successful implantation and establishment of pregnancy requires a delicate balance between embryo development and uterine receptivity. FET cycles mostly get canceled when EMT on the day of progesterone administration remains below 8 mm. However, there exist patients who have recurrently failed to achieve the desired thickness; no optimal regimen for these patients has yet been determined.
GH has been suggested to improve endometrial receptivity in patients with poor endometrial condition. In one case report, a patient with pituitary resection had undergone recurrent IVF failures due to inadequate endometrial development. After GH-replacement therapy, the thickness improved, and eventually, a twin pregnancy was successfully delivered. Yu et al. had conducted intrauterine perfusion of rhGH for endometrial preparation in five patients with thin endometrium; as a result, the clinical outcome improved. In a retrospective analysis of 1,114 infertile women, GH was found to be associated with greater EMT, better implantation, and higher pregnancy rates. A prospective clinical trial reported that addition of GH to the artificial cycle of FET could increase EMT and blood flow, ultimately leading to a better clinical outcome. Cui et al. found that GH could increase the EMT in patients with thin endometrium and promote endometrial cell proliferation in vitro. However, the dosage and usage of GH vary in different studies. Because of the limited experience with the above-mentioned protocols for GH administration, there is a lack of evidence to support the superiority of one method over the other. We had the same dose of GH as Du et al. To the best of our knowledge, this is the first research to begin GH from progesterone day. Because GHR was found to be expressed in glandular cells of the human endometrium in the luteal phase, we speculated that this method of GH addition might facilitate implantation. The relatively lower dose and shorter duration of GH administration would be more safe and cost-effective.
Furthermore, the mechanism of GH in the human endometrium remains largely unknown. Because we excluded the impact of embryo quality and maternal age, the underlying biological mechanism seems to be related to endometrial receptivity, which implies that rhGH might improve the endometrial receptivity through blood flow or at molecular level. Maternal expression of growth factors and cell adhesion molecules play a major role in the phenomenon of implantation. GH might regulate cytokines produced by the uterus, enhancing endometrial receptivity by controlling the expression of adhesion and anti-adhesion proteins. Cui et al. offered the evidence that GH can act in a direct or IGF-1-mediated manner to upregulate receptivity-related molecules expression.
There are some critical limitations of this observational study. As a retrospective analysis, it was hardly possible to avoid bias. First, there was patient selection bias without randomization and blinding. Second, we did not achieve the optimal sample size in two treatment entities, with GH group size being much bigger than that of control (a ratio of approximately 3:1). Especially when we conducted subgroup analyses, the case number per group was remarkably reduced.
In conclusion, these data provided substantial evidence to indicate that rhGH can improve clinical outcomes after FET. Further prospective studies and randomized controlled trials would be required in future, for more detailed information about the correlation between rhGH and endometrium.
We acknowledge the help of all the staff and patients from Shanghai JI AI Genetics and IVF Institute.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Calhazjorge C, de Geyter C, Kupka MS, de Mouzon J, Erb K, Mocanu E, et al.
Assisted reproductive technology in Europe, 2012: results generated from European registers by ESHRE. Hum Reprod 2016;21:1680. doi: 10.1093/humrep/dew151.
Norwitz ER, Schust DJ, Fisher SJ. Implantation and the survival of early pregnancy. N Engl J Med 2001;345:1400-8. doi: 10.1056/NEJMra000763.
Hertz-Picciotto I, Samuels SJ. Incidence of early loss of pregnancy. N Engl J Med 1988;319:1483-4. doi: 10.1056/NEJM198812013192214.
Miravet-Valenciano JA, Rincon-Bertolin A, Vilella F, Simon C. Understanding and improving endometrial receptivity. Curr Opin Obstet Gynecol 2015;27:187-92. doi: 10.1097/gco.0000000000000173.
Navot D, Scott RT, Droesch K, Veeck LL, Liu HC, Rosenwaks Z. The window of embryo transfer and the efficiency of human conception in vitro
. Fertil Steril 1991;55:114-8. doi: 10.1016/S0015-0282(16)54069-2.
Duc-Goiran P, Mignot TM, Bourgeois C, Ferré F. Embryo-maternal interactions at the implantation site: A delicate equilibrium. Eur J Obstet Gynecol Reprod Biol 1999;83:85-100. doi: 10.1016/S0301-2115(98)00310-8.
Hofmann GE, Thie J, Scott RT Jr., Navot D. Endometrial thickness is predictive of histologic endometrial maturation in women undergoing hormone replacement for ovum donation. Fertil Steril 1996;66:380-3. doi: 10.1016/S0015-0282(16)58504-5.
Isaacs JD Jr., Wells CS, Williams DB, Odem RR, Gast MJ, Strickler RC. Endometrial thickness is a valid monitoring parameter in cycles of ovulation induction with menotropins alone. Fertil Steril 1996;65:262-6. doi: 10.1016/S0015-0282(16)58082-0.
McWilliams GD, Frattarelli JL. Changes in measured endometrial thickness predict in vitro
fertilization success. Fertil Steril 2007;88:74-81. doi: 10.1016/j.fertnstert.2006.11.089.
Mahajan N, Sharma S. The endometrium in assisted reproductive technology: How thin is thin? J Hum Reprod Sci 2016;9:3-8. doi: 10.4103/0974-1208.178632. [Full text]
Dickey RP, Olar TT, Taylor SN, Curole DN, Matulich EM. Relationship of endometrial thickness and pattern to fecundity in ovulation induction cycles: Effect of clomiphene citrate alone and with human menopausal gonadotropin. Fertil Steril 1993;59:756-60. doi: 10.1016/S0015-0282(16)55855-5.
Senturk LM, Erel CT. Thin endometrium in assisted reproductive technology. Curr Opin Obstet Gynecol 2008;20:221-8. doi: 10.1097/GCO.0b013e328302143c.
Zhang T, Li Z, Ren X, Huang B, Zhu G, Yang W, et al.
Endometrial thickness as a predictor of the reproductive outcomes in fresh and frozen embryo transfer cycles: A retrospective cohort study of 1512 IVF cycles with morphologically good-quality blastocyst. Medicine (Baltimore) 2018;97:e9689. doi: 10.1097/md.0000000000009689.
El-Toukhy T, Coomarasamy A, Khairy M, Sunkara K, Seed P, Khalaf Y, et al.
The relationship between endometrial thickness and outcome of medicated frozen embryo replacement cycles. Fertil Steril 2008;89:832-9. doi: 10.1016/j.fertnstert.2007.04.031.
Kasius A, Smit JG, Torrance HL, Eijkemans MJ, Mol BW, Opmeer BC, et al.
Endometrial thickness and pregnancy rates after IVF: A systematic review and meta-analysis. Hum Reprod Update 2014;20:530-41. doi: 10.1093/humupd/dmu011.
Gleicher N, Vidali A, Barad DH. Successful treatment of unresponsive thin endometrium. Fertil Steril 2011;95:2123.e13-7. doi: 10.1016/j.fertnstert.2011.01.143.
Takasaki A, Tamura H, Miwa I, Taketani T, Shimamura K, Sugino N. Endometrial growth and uterine blood flow: A pilot study for improving endometrial thickness in the patients with a thin endometrium. Fertil Steril 2010;93:1851-8. doi: 10.1016/j.fertnstert.2008.12.062.
Hull KL, Harvey S. Growth hormone: Roles in female reproduction. J Endocrinol 2001;168:1-23. doi: 10.1385/ENDO:13:3:243.
Tesarik J, Hazout A, Mendoza C. Improvement of delivery and live birth rates after ICSI in women aged >40 years by ovarian co-stimulation with growth hormone. Hum Reprod 2005;20:2536-41. doi: 10.1093/humrep/dei066.
Yovich JL, Stanger JD. Growth hormone supplementation improves implantation and pregnancy productivity rates for poor-prognosis patients undertaking IVF. Reprod Biomed Online 2010;21:37-49. doi: 10.1016/j.rbmo.2010.03.013.
Eftekhar M, Aflatoonian A, Mohammadian F, Eftekhar T. Adjuvant growth hormone therapy in antagonist protocol in poor responders undergoing assisted reproductive technology. Arch Gynecol Obstet 2013;287:1017-21. doi: 10.1007/s00404-012-2655-1.
Groenewoud ER, Cohlen BJ, Macklon NS. Programming the endometrium for deferred transfer of cryopreserved embryos: Hormone replacement versus modified natural cycles. Fertil Steril 2018;109:768-74. doi: 10.1016/j.fertnstert.2018.02.135.
Gardner DK, Lane M, Schoolcraft WB. Physiology and culture of the human blastocyst. J Reprod Immunol 2002;55:85-100. doi: 10.1016/S0165-0378(01)00136-X.
Malizia BA, Hacker MR, Penzias AS. Cumulative live-birth rates after in vitro
fertilization. N Engl J Med 2009;360:236-43. doi: 10.1056/NEJMoa0803072.
Harper MJ. The implantation window. Baillieres Clin Obstet Gynaecol 1992;6:351-71. doi: 10.1016/S0950-3552(05)80092-6.
Drakopoulos P, Pluchino N, Bischof P, Cantero P, Meyer P, Chardonnens D. Effect of growth hormone on endometrial thickness and fertility outcome in the treatment of women with panhypopituitarism: A case report. J Reprod Med 2016;61:78-82.
Yu H, Gao S, Tang H, Chen H, Deng Z, Yang L, et al.
Growth hormone intrauterine perfusion combined with replacement cycle in the treatment of non-response thin endometrium – Report of 5 cases. Int J Clin Exp Med 2016;9:11982-9.
Du XF, Yang XH, Li J, Hao M, Guo YH. Growth hormone co-treatment within a GnRH agonist long protocol improves implantation and pregnancy rates in patients undergoing IVF-ET. Arch Gynecol Obstet 2016;294:877-83. doi: 10.1007/s00404-016-4163-1.
Xue-Mei W, Hong J, Wen-Xiang Z, Yang L. The effects of growth hormone on clinical outcomes after frozen-thawed embryo transfer. Int J Gynaecol Obstet 2016;133:347-50. doi: 10.1016/j.ijgo.2015.10.020.
Cui N, Li AM, Luo ZY, Zhao ZM, Xu YM, Zhang J, et al.
Effects of growth hormone on pregnancy rates of patients with thin endometrium. J Endocrinol Invest 2019;42:27-35. doi: 10.1007/s40618-018-0877-1.
Sbracia M, Scarpellini F, Poverini R, Alò PL, Rossi G, Di Tondo U. Immunohistochemical localization of the growth hormone in human endometrium and decidua. Am J Reprod Immunol 2004;51:112-6. doi: 10.1046/j.8755-8920.2003.00127.x.
Simón C, Martín JC, Pellicer A. Paracrine regulators of implantation. Baillieres Best Pract Res Clin Obstet Gynaecol 2000;14:815-26. doi: 10.1053/beog.2000.0121.
[Table 1], [Table 2], [Table 3]