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| ORIGINAL ARTICLE |
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| Year : 2016 | Volume
: 3
| Issue : 3 | Page : 90-97 |
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Role of testosterone pretreatment in poor ovarian responders undergoing in vitro fertilization/intracytoplasmic injection in comparison with growth hormone
Pratibha Vishwakarma, Indumathi Joy, Thankam R Varma
Institute of Reproductive Medicine and Women's Health, Madras Medical Mission Hospital, Chennai, Tamil Nadu, India
| Date of Web Publication | 21-Apr-2017 |
Correspondence Address:
Pratibha Vishwakarma
H. No. 1/2641, Street No. 3, Loni Road, Ram Nagar, Shahdara, New Delhi - 110 032
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2348-2907.204667
Objective: Androgen can play a synergistic role with follicle-stimulating hormone in promoting the early follicular recruitment, which is critical in Assisted Reproduction Technique program. In patients with poor ovarian response (POR) and poor ovarian reserve may benefit from testosterone gel application and growth hormone. This study was done to assess whether poor responders can benefit from androgen therapy before in vitro fertilization/intracytoplasmic sperm injection and from growth hormone. Study Design: It is a prospective pilot study on 35 patients with previous POR and poor ovarian reserve attending IRM, OPD between January 2015 and December 2015 for 1 year. Materials and Methods: Selected women received transdermal therapy of testosterone gel 12.5 mg over the skin of shoulder and upper arm for 21 days from day 7 to day 27 of cycle during oral contraceptive pills if the cycle was not regular and gel treatment before gonadotropin stimulation cycle for next one cycle. Hormone assessment (total testosterone, sex hormone-binding globulins, and androstenedione level) was done at the beginning and at the end of the gel application. Ovarian stimulation with fixed antagonist protocol was used. The primary outcome is improvement in antral follicle count (AFC), the total number of oocyte retrieved, number of mature oocytes, and good quality of embryos. In this study, implantation rate and clinical pregnancy rate were also assessed. If patient did not respond to testosterone gel, growth hormone was used in next cycle with gonadotropins and same parameters were used. Results: In this study, we found that two drugs are comparable in terms of clinical pregnancy rate, ongoing pregnancy rate, and live-birth rate. We found that number of cryopreserved embryos and cumulative pregnancy rate are more in testosterone group. Fertilization rate and cleavage arrest were similar in both groups. Cancellation rate was less, and duration of gonadotropins treatment was more in testosterone-only group. Significantly increased androstenedione level was seen in improved cycles of testosterone gel treatment. Out of 35 patients with testosterone gel treatment, in 42.9% cases, AFC improved. Conclusion: Testosterone gel treatment is useful in patients with poor ovarian reserve or poor ovarian responders in terms of improving AFC, more number of oocytes, increased number of embryos and increased number of cryopreserved embryos, and hence cumulative pregnancy rate. Growth hormone had equivalent results with testosterone gel with less number but good-quality oocytes and embryos. This is a pilot study, including a small number of patients; hence, further randomized trials are needed before using expensive and injectable drug, i.e., growth hormone in poor responders.
Keywords: Growth hormone, in vitro fertilization, poor ovarian reserve, poor responders, testosterone gel
How to cite this article:
Vishwakarma P, Joy I, Varma TR. Role of testosterone pretreatment in poor ovarian responders undergoing in vitro fertilization/intracytoplasmic injection in comparison with growth hormone. IVF Lite 2016;3:90-7 |
How to cite this URL:
Vishwakarma P, Joy I, Varma TR. Role of testosterone pretreatment in poor ovarian responders undergoing in vitro fertilization/intracytoplasmic injection in comparison with growth hormone. IVF Lite [serial online] 2016 [cited 2023 Jun 6];3:90-7. Available from: http://www.ivflite.org/text.asp?2016/3/3/90/204667 |
| Introduction | |  |
Assisted reproductive technologies (ARTs) are being increasingly used in infertility treatment. ARTs imply the pharmacological induction of multiple follicular recruitment to obtain multiple oocytes and embryos. The most widely used protocol for ovarian stimulation in ART cycles has involved the administration of gonadotropins under pituitary suppression with GnRH agonists (the so-called “long down-regulation protocol”), which not only increases pregnancy and live-birth rates but also allows flexible timing for oocyte recovery and greatly simplifies in vitro fertilization (IVF) treatment.[1],[2],[3] However, many women are found to respond poorly or not at all to this standard treatment. Such patients are referred to as “low or poor responders,” and the incidence of low responders is estimated to be 10%–25% of the ART population.[4],[5],[6],[7] Low response to ovarian stimulation frequently reflects an age-related decline in reproductive performance (older patients with an abnormal endocrinological profile), but the same phenomenon may occur in young patients.[6],[7] Some of the latter group of women have so-called “occult ovarian failure” evidenced by elevated follicle-stimulating hormone (FSH) serum concentrations,[8] but others have normal serum FSH and no apparent reason for repeated low responses to aggressive stimulation protocols.[6],[7] Since the evolution of ART, the management of these younger women with normal hormonal profile has been one of the most difficult challenges and disappointing issues in reproductive medicine. In fact, it has been stressed that irrespective of the protocol used, the treatment of poor responders (including the idiopathic group with no defined risks) results in a low pregnancy rate unless the couple makes the difficult decision to use donor oocytes.[4],[7],[9],[10] Serum testosterone (T) decreases as age advances in premenopausal women,[11],[12],[13],[14] paralleling a similar age-related decline of antral follicle count (AFC), and level of anti-mullerian hormone (AMH). Because it has been found that the T response to human chorionic gonadotropin (hCG) decreases with age,[15] it is assumed that there is an age-related decrease of T secretion from the theca tissue surrounding ovarian follicles. In a study of 425 normally cycling women,[11] baseline T remained correlated with the number of retrieved oocytes after adjusting by logistic regression analysis for age, body mass index (BMI), smoking, and timing of the sample during the menstrual cycle. These findings suggest that ovarian T plays a role in the ability of follicles to respond to FSH and that part of the decreased ovarian response with aging may be due to declining ovarian androgen production. Altogether, these studies suggest that androgen treatment may amplify the FSH effects on the ovary. In the clinical setting, it was reported that dehydroepiandrosterone [16] or letrozole (an aromatase inhibitor which induces a temporary accumulation of intraovarian androgens)[17],[18] supplementation improved the estradiol (E2) and/or follicular response to gonadotropin treatment. In addition, two recent studies have reported a positive correlation of serum testosterone levels with some, but not all, parameters of ovarian stimulation in IVF cycles.[11],[19] Growth hormone supplements have long been part of the adjunctive therapy offered in case of poor ovarian response (POR) to controlled ovarian stimulation (COS) protocols.[20],[21] Recently, three meta analyses [21],[22],[23] reviewed the value of providing GH supplements during treatment with assisted reproductive techniques (ART). Each study independently concluded that GH cotreatment generally benefits women with POR to common ART treatments. In spite of these findings, the issue of GH use in ART has remained somewhat controversial, and GH appears to be underprescribed. On the above evidence, this prospective study was undertaken to investigate the usefulness of testosterone pretreatment in women with normal FSH serum concentrations who had two consecutive canceled IVF cycles because of insufficient ovarian response in spite of vigorous gonadotropin ovarian stimulation and in women with poor ovarian reserve.
| Materials and Methods | | |
It is a prospective, pilot study on 35 patients with previous POR and poor ovarian reserve attending IRM, OPD between January 2015 and December 2015 for 1 year.
Patients studied
- Inclusion criteria
- Patients with previous POR, i.e., <3 follicles, >18 mm with a two conventional stimulation protocol, in the absence of advanced maternal age, and other decreased ovarian reserve tests.
- Patients with decreased ovarian response according to ESHRE criteria, i.e., if two out of 3 features are present:
- Advanced maternal age (>40 years) or any other risk factors for poor ovarian reserve
- A previous ovarian response (<3 oocytes with a conventional stimulation protocol)
- An abnormal ovarian reserve tests, i.e., AFC 5–7 follicles or AMH <0.5–1.1 ng/ml.
- Exclusion criteria
- Women >40 years
- History of endocrine and metabolic disorders
- Patients with premature ovarian failure due to genetic causes
- Women with previous pelvic surgeries.
All patients gave informed consent to participate in the study. The period between the first and third IVF cycle was always within 13 months. All the patients were regularly menstruating (menstrual cycles of 25–35 days). All the women had both ovaries, no previous ovarian surgery, and normal ovulatory function according to regular menses. None of them had occult ovarian failure on the basis of their basal FSH concentration of <10 IU/L, measured in the cycle preceding IVF.
Method of testosterone gel treatment
Testosterone therapy was commenced the day when pituitary–ovarian suppression was confirmed. Selected women received transdermal therapy of testosterone gel 12.5 mg over the skin of shoulder and upper arm for 21 days from day 7 to day 27 of the cycle during oral contraceptive pills if the cycle was <28 days (to complete the gel treatment) before gonadotropin stimulation cycle for next one cycle.
Stimulation protocol
After the testosterone gel treatment, on day 2 of menses, AFC was assessed to see the improvement. At least, 3 more antral follicle than the previous count was considered as improved as we did not go for IVF if AFC was <3. Gonadotropin stimulation of the ovaries was started when serum estradiol (E2) concentrations declined to 50 pg/ml, and a vaginal ultrasonic scan showed an absence of follicles >10 mm diameter. In patients with improved AFC, ovarian stimulation with fixed antagonist protocol was used. Recombinant FSH (rFSH) 300 U and HP hMG 150 U were given for initial 5 days, and dose was adjusted according to the response as assessed by sequential transvaginal ultrasonography and serum E2 measurements. From day 5 onward, hMG was administered on an individual basis according to the ovarian response. GnRH antagonist was started from day 6 along with the gonadotropins till hCG trigger. The criteria for hCG administration (urinary hCG 10,000 U, IM) were the presence of >2 follicles ≥18 mm in diameter with >4 follicles measuring >14 mm in association with consistent rise in serum E2 level. The cycle would be canceled when there are <3 follicles with diameter <14 mm after 8–9 days of gonadotropin stimulation (early cancellation) or after 4–5 additional treatment days with attaining or imminent prospect of attaining the criteria for hCG administration (late cancelation). E2 level was measured on hCG trigger. If the patient did not respond to testosterone gel, growth hormone was used in next cycle, and same parameters were used. Growth hormone 8 units, subcutaneously, were given along with gonadotropins till hCG trigger. Oocyte aspiration was performed with vaginal ultrasonography 36 h after hCG administration. Intracytoplasmic sperm injection was performed irrespective of male factor. Embryo grading was recorded according to published criteria;[24] embryos of grades 1 or 2 were considered high quality. Two to three days after oocyte recovery, up to four embryos per patient (depending on the age of the patient, the indication for IVF and the number and quality of embryos available per replacement) were replaced. Injectable progesterone daily was given to supplement the luteal phase. Pregnancy was diagnosed by increasing serum concentrations of hCG after embryo transfer and the subsequent demonstration of an intrauterine gestational sac by ultrasonography.
Outcome measures
The primary outcome is improvement in AFC, the total number of oocyte retrieved, number of mature oocytes, and good quality of embryos. In this study, fertilization rate, implantation rate, clinical pregnancy rate, ongoing pregnancy rate, live birth rate, and cancellation rate were also assessed.
Monitoring, hormone analyses, and ultrasonography
Baseline hormone assessment (FSH, luteinizing hormone [LH], AMH, and E2) was assessed in testosterone gel treatment cycle and in stimulation cycle. Hormone assessment (total testosterone, sex hormone-binding globulins [SHBGs], and androstendione level) was done at the beginning, i.e., from day 1 to day 6 of testosterone gel cycle and at the end of the gel application, i.e., at day 28. FSH, LH, and E2 level were assessed by enhanced chemiluminescence immunoassay (CLIA) method. The AMH was assessed by Gen II ELISA method which is an enzymatically amplified two-site immunoassay. Cutoff point for poor ovarian reserve was <1.1 ng/ml. SHBG and total testosterone were analyzed by chemiluminescence microparticle immune assay (CMIA) method, and serum androstenedione was analyzed by CLIA method. The reference range for premenopausal women for SHBG, total testosterone, and androstenedione was 19.8–155.2 nmol/L, 10.83–55.94 ng/dl, and 0.3–3.1 ng/ml, respectively. Ultrasound machine used for scan was from Philips company using 6.5 mHz probe for scan. The numbers of follicles in both ovaries were added for the total AFC. The follicles visualized and counted by transvaginal sonography in the early follicular phase were 2–10 mm in size. This is based on the finding that follicle size can vary up to 10 mm before the dominant follicle is identified and by including follicles up to 10 mm, the antral follicle cohort is determined at its maximal size. The limit of sensitivity was 2 mm.
Statistical analysis
Data were analyzed by using the Mann–Whitney U-test, Welch test, and Chi-square test as appropriate. The results are expressed as mean ± standard deviation. P< 0.05 was considered statistically significant.
| Results | | |
All 35 patients were divided into two groups, i.e., in Group 1, patients not responded to testosterone treatment followed by injection growth hormone (n = 15) and the patients took only testosterone gel treatment (n = 20).
As presented in [Table 1], the main demographic and baseline characteristics of the patients in Groups 1 and 2 were very similar, including age, BMI, causes and duration of infertility, basal FSH, LH, and E2 serum levels, and the AFC at baseline. Analysis of gonadotropin treatment and ovarian response shows that the duration of gonadotropin ovarian stimulation significantly lower in Group 1 (9.76 ± 2.25 vs. 11.71 ± 2.62 days; P= 0.027), whereas the total amount of gonadotropin used was similar in both groups. Total number of oocytes (37 vs. 39; P= 0.0137and total number of embryos (3.27 ± 1.10 vs. 6.0 ± 3.16; P= 0.002) were more in Group 2 significantly [Table 2]. Cancellation rate was significantly less in Group 2 means patients reaching to ovum pick up was significantly more in Group 2 [Table 3].
In this study, it was seen that serum androstenedione level (2.27 ± 1.42 vs. 1.31 ± 1.06) was significantly more in improved cycles [Table 4]. Day 2 transfer was significantly more in Group 1. The fresh cycle was performed significantly more in Group 1. Cyopreserved embryos were more in Group 2 showing higher cumulative pregnancy rate. No significant differences were found for any of the remaining variables investigated. No adverse effect, systemic or on application site of the testosterone gel, and growth hormone was reported, and no other practical difficulties related to the specific purposes of this study were encountered.
| Discussion | | |
Several strategies have been proposed to improve outcome in low responders but unfortunately, all of these approaches have met with only limited success, and to date, no compelling advantage for one stimulation protocol over another has been established.[4],[7],[9],[10]
The concept that androgens are atretogenic was derived from murine ovary studies, and this has been challenged by recent work in primates showing that androgens may have, in fact, some synergistic effects with FSH on follicular growth and development.[25],[26],[27],[28]
It has been shown that for successful induction of multiple folliculogenesis in normally ovulating women, there is a critical period during the early follicular phase of the cycle when FSH values should remain above the physiological level to maximally stimulate follicle recruitment in the primary cohort.[29],[30] Follicles recruited by exogenous FSH require an FSH threshold concentration that is higher than that in the natural cycle.[30] Marked patient variability exists in FSH thresholds as well as in FSH metabolic clearance and ovarian sensitivity to FSH.[31],[32],[33] That is why few patients respond poorly to standard ovarian stimulation protocol.
In this pilot study, according to the above evidence, we used high doses, i.e., 450 U of gonadotropins (FSH and LH) to recruit more and more follicles. Although follicular growth can be induced by FSH alone, it needs the LH threshold for proper development. Ovulation induction studies in hypogonadotropic women using rFSH have demonstrated that FSH can induce follicular growth to the preovulatory stage, but E2 and androstenedione concentration remain extremely low.[34],[35] There is, however, some evidence to suggest that LH has benefits in women aged above 35 years and in poor or suboptimal responders to COS.[36] However, at present, the possibility that androgen treatment directly [37],[38],[39] or indirectly through the use of an aromatase inhibitor (which induces a temporary accumulation of intraovarian androgens)[18],[40] or recombinant LH (considering that androgens are direct secretory product of LH action on theca cells),[41] may amplify the FSH effects on the ovary, improving follicular recruitment, is a matter of great interest and research. We demonstrate a potential benefit of testosterone and growth hormone treatment in improving ovarian response to FSH stimulation in the previous poor responders to vigorous gonadotropin treatment for IVF.
The following facts support this contention. First, as much as 42.9% of patients improved their AFC after testosterone gel treatment. Second, 100% patients with improved AFC who went for IVF underwent oocyte retrieval. However, the total duration of gonadotropins treatment was more as compared to treatment with growth hormone. Third, number of cryopreserved embryos (33.3%/case) and cumulative pregnancy were more in Group 2 significantly. Finally, androgen treatment promoted FSH action in those recruitable follicles as suggested by increased serum levels of androstenedione considered as markers of ovarian responsiveness to gonadotropin stimulation in improved versus nonimproved testosterone supplemented IVF cycles. In discussing GH for POR and poor ART outcome, the initial Cochrane meta-analysis and basic studies showing positive effects of GH on granulosa cells.[42] Since that editorial, the meta-analyses by Kyrou et al., 2009 and by Kolibianakis et al. in human reproduction update further supported higher pregnancy and delivery rates in GH-treated patients. Tesarik et al., 2005[43] reported similar improvements in very low prognosis women older than age 40 years (POR/AO), but their data were not included in the meta-analyses because their patients were not defined as frank POR. In spite of the accumulating information on GH use in ART, we suspected that GH is still not widely used in POR. It is likely that the lack of regulatory approval and pharmaceutical industry promotion of this indication continues to lead to underutilization of this adjunct. The reputation of GH treatment stemming from abuse by athletes and body builders may also be a contributing factor [Table 5].[44],[45],[46],[47]
We, therefore, concur with the conclusions of the authors of the meta-analyses that further trials are urgently needed. Ultimately while waiting for the much-needed studies, she or he will make the lonely decision, with informed consent, to use or not to use GH cotreatment in poor ART performers. In our eyes, combining a GH supplement with a proven poor-response protocol is clinically sound and mindful of the accumulated evidence.
The current study has several potential limitations but also some strengths. As this is a pilot study including small number of patients, but it is a prospective study. Frozen cycles were more in Group 2 significantly which can affect the pregnancy rate. There is evidence that endometrial receptivity may be negatively affected by ovarian stimulation.[48],[49] A recent randomized controlled trial has suggested that there may be an advantage to freezing all blastocyst in the fresh cycle and replacing them in a natural or downregulated cycle.[50],[51] The finding of significantly improved pregnancy rate in a cryopreserved blastocyst cycle compared to the fresh cycle may be due to the improved endometrial receptivity and endometrial and embryo synchronization. However, in patients with POR hormonal milieu is not that much detrimental. Fifteen patients out of 35 did not go for further treatment because of disappointment with no improvement. Out of these 15 patients, 5 had improved AFC after the testosterone gel treatment, but they did not go for IVF due to unaffordability.
Testosterone gel pretreatment is useful in patients with poor ovarian reserve or poor ovarian responders in terms of improving antral follicular count and more number of oocytes and embryos. This treatment is also improving cryopreserved embryos per case and hence cumulative pregnancy rate per case. Growth hormone had comparable fertilization rate, cleavage arrest rate, implantation rate, clinical pregnancy rate and live birth rate with Testosterone gel. In our study, we found that these two treatments were beneficial for patients with poor ovarian responders and with poor ovarian reserves. This is a pilot study including a small number of patients, hence further randomized trials are needed before using expensive and injectable drug i.e. growth hormone in poor responders.
Acknowledgment
We greatly acknowledge the participation of Dr. Arun Kumar for his help in collecting the articles and Dr. Rajeev Kumar Malhotra (Professor in Biostatistics) for his precious work in statistics.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no confl icts of interest.
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| 51. | Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C, Thomas S. Evidence of impaired endometrial receptivity after ovarian stimulation for in vitro fertilization: A prospective randomized trial comparing fresh and frozen-thawed embryo transfer in normal responders. Fertil Steril 2011;96:344-8. |
| Authors | | |
 MBBS, MS (Obst & Gynae), Post doctoral fellow in Reproductive Medicine (FNB). Published papers: A-Ultrasonographic and Endoscopic evaluation in infertility (Journal of UPCOG in 2009). B-Successful preventive treatment of congenital heart block during pregnancy in a woman with systemic lupus erythematosus with anti La/ Ro antibody-case report (The Journal of Obstetrics and Gynecology of India, 66(2), 598-600,http://link.springer. com/article/10.1007/s13224-016-0844-8). C-Enlarged Ovaries Following IVF/ICSI as an Etiology of Obstructive Uropathy Resulting in Acute Renal Failure: A case Report (Indian Journal of Clinical Practice,Vol.26,no.9,February 2016). D-To compare the effectiveness of recombinant gonadotropin versus the combination of recombinant follicle stimulating hormone and highly purifi ed human menopausal gonadotropin versus urinary human menopausal gonadotropin alone for ovarian stimulation in women undergoing in vitro fertilization or intra cytoplasmic sperm injection treatment cycles-A retrospective study,(International Journal of Reproduction,Contraception,Obstetrics and Gynecology in June 2016).
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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