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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 3  |  Page : 90-97

Role of testosterone pretreatment in poor ovarian responders undergoing in vitro fertilization/intracytoplasmic injection in comparison with growth hormone


Institute of Reproductive Medicine and Women's Health, Madras Medical Mission Hospital, Chennai, Tamil Nadu, India

Date of Web Publication21-Apr-2017

Correspondence Address:
Pratibha Vishwakarma
H. No. 1/2641, Street No. 3, Loni Road, Ram Nagar, Shahdara, New Delhi - 110 032
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2348-2907.204667

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  Abstract 


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 Nov 28];3:90-7. Available from: http://www.ivflite.org/text.asp?2016/3/3/90/204667




  Introduction Top


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 Top


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


    1. 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.
    2. Patients with decreased ovarian response according to ESHRE criteria, i.e., if two out of 3 features are present:


    1. Advanced maternal age (>40 years) or any other risk factors for poor ovarian reserve
    2. A previous ovarian response (<3 oocytes with a conventional stimulation protocol)
    3. An abnormal ovarian reserve tests, i.e., AFC 5–7 follicles or AMH <0.5–1.1 ng/ml.


  • Exclusion criteria


  1. Women >40 years
  2. History of endocrine and metabolic disorders
  3. Patients with premature ovarian failure due to genetic causes
  4. 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 Top


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].
Table 1: Basal characteristics in both groups

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Table 2: Oocyte and embryo quality in two group

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Table 3: Clinical variables in treatment cycle

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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.
Table 4: Hormone level in improved and nonimproved cycle

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  Discussion Top


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]
Table 5: Outcome in testosterone treatment cycle

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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.



 
  References Top

1.
Daya S. Optimal protocol for gonadotropin releasing hormone agonist use in ovarian stimulation. In: Gomel V, Cheung PC, editors.In vitro Fertilization and Assisted Reproduction. Bologna, Italy: Monduzzi Editore; 1997. p. 405-15.  Back to cited text no. 1
    
2.
Daya S. Gonadotropin releasing hormone agonist protocols for pituitary desensitization in in vitro fertilization and gamete intrafallopian transfer cycles. Cochrane Database Syst Rev 2000;2:CD001299.  Back to cited text no. 2
    
3.
Barbieri RL, Hornstein MD. Assisted reproduction-in vitro fertilization success is improved by ovarian stimulation with exogenous gonadotropins and pituitary suppression with gonadotropin-releasing hormone analogues. Endocr Rev 1999;20:249-52.  Back to cited text no. 3
    
4.
Keay SD, Liversedge NH, Mathur RS, Jenkins JM. Assisted conception following poor ovarian response to gonadotrophin stimulation. Br J Obstet Gynaecol 1997;104:521-7.  Back to cited text no. 4
    
5.
Karande V, Gleicher N. A rational approach to the management of low responders in in-vitro fertilization. Hum Reprod 1999;14:1744-8.  Back to cited text no. 5
    
6.
Fasouliotis SJ, Simon A, Laufer N. Evaluation and treatment of low responders in assisted reproductive technology: A challenge to meet. J Assist Reprod Genet 2000;17:357-73.  Back to cited text no. 6
    
7.
Tarlatzis BC, Zepiridis L, Grimbizis G, Bontis J. Clinical management of low ovarian response to stimulation for IVF: A systematic review. Hum Reprod Update 2003;9:61-76.  Back to cited text no. 7
    
8.
Cameron IT, O'Shea FC, Rolland JM, Hughes EG, de Kretser DM, Healy DL. Occult ovarian failure: A syndrome of infertility, regular menses, and elevated follicle-stimulating hormone concentrations. J Clin Endocrinol Metab 1988;67:1190-4.  Back to cited text no. 8
    
9.
Surrey ES, Schoolcraft WB. Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques. Fertil Steril 2000;73:667-76.  Back to cited text no. 9
    
10.
Mahutte NG, Arici A. Poor responders: Does the protocol make a difference? Curr Opin Obstet Gynecol 2002;14:275-81.  Back to cited text no. 10
    
11.
Barbieri RL, Sluss PM, Powers RD, McShane PM, Vitonis A, Ginsburg E, et al. Association of body mass index, age, and cigarette smoking with serum testosterone levels in cycling women undergoing in vitro fertilization. Fertil Steril 2005;83:302-8.  Back to cited text no. 11
    
12.
Sowers MF, Beebe JL, McConnell D, Randolph J, Jannausch M. Testosterone concentrations in women aged 25-50 years: Associations with lifestyle, body composition, and ovarian status. Am J Epidemiol 2001;153:256-64.  Back to cited text no. 12
    
13.
Qin Y, Zhao Z, Sun M, Geng L, Che L, Chen ZJ. Association of basal serum testosterone levels with ovarian response and in vitro fertilization outcome. Reprod Biol Endocrinol 2011;9:9.  Back to cited text no. 13
    
14.
Frattarelli JL, Gerber MD. Basal and cycle androgen levels correlate with in vitro fertilization stimulation parameters but do not predict pregnancy outcome. Fertil Steril 2006;86:51-7.  Back to cited text no. 14
    
15.
Piltonen T, Koivunen R, Ruokonen A, Tapanainen JS. Ovarian age-related responsiveness to human chorionic gonadotropin. J Clin Endocrinol Metab 2003;88:3327-32.  Back to cited text no. 15
    
16.
Casson PR, Lindsay MS, Pisarska MD, Carson SA, Buster JE. Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: A case series. Hum Reprod 2000;15:2129-32.  Back to cited text no. 16
    
17.
Mitwally MF, Casper RF. Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders. Fertil Steril 2002;77:776-80.  Back to cited text no. 17
    
18.
Garcia-Velasco JA, Moreno L, Pacheco A, Guillé n A, Duque L, Requena A, et al. The aromatase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilization outcome in low responder patients: A pilot study. Fertil Steril 2005;84:82-7.  Back to cited text no. 18
    
19.
Frattarelli JL, Peterson EH. Effect of androgen levels on in vitro fertilization cycles. Fertil Steril 2004;81:1713-4.  Back to cited text no. 19
    
20.
Meldrum DR, Chang RJ, de Ziegler D, Schoolcraft WB, Scott RT Jr., Pellicer A. Adjuncts for ovarian stimulation: When do we adopt “orphan indications” for approved drugs? Fertil Steril 2009;92:13-8.  Back to cited text no. 20
    
21.
Kyrou D, Kolibianakis EM, Venetis CA, Papanikolaou EG, Bontis J, Tarlatzis BC. How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: A systematic review and meta-analysis. Fertil Steril 2009;91:749-66.  Back to cited text no. 21
    
22.
Duffy JM, Ahmad G, Mohiyiddeen L, Nardo LG, Watson A. Growth hormone for in vitro fertilization. Cochrane Database Syst Rev 2010;(1):CD000099.  Back to cited text no. 22
    
23.
Kolibianakis EM, Venetis CA, Diedrich K, Tarlatzis BC, Griesinger G. Addition of growth hormone to gonadotrophins in ovarian stimulation of poor responders treated by in-vitro fertilization: A systematic review and meta-analysis. Hum Reprod Update 2009;15:613-22.  Back to cited text no. 23
    
24.
Van Royen E, Mangelschots K, De Neubourg D, Valkenburg M, Van de Meerssche M, Ryckaert G, et al. Characterization of a top quality embryo, a step towards single-embryo transfer. Hum Reprod 1999;14:2345-9.  Back to cited text no. 24
    
25.
Vendola KA, Zhou J, Adesanya OO, Weil SJ, Bondy CA. Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest 1998;101:2622-9.  Back to cited text no. 25
    
26.
Vendola K, Zhou J, Wang J, Famuyiwa OA, Bievre M, Bondy CA. Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary. Biol Reprod 1999;61:353-7.  Back to cited text no. 26
    
27.
Weil SJ, Vendola K, Zhou J, Adesanya OO, Wang J, Okafor J, et al. Androgen receptor gene expression in the primate ovary: Cellular localization, regulation, and functional correlations. J Clin Endocrinol Metab 1998;83:2479-85.  Back to cited text no. 27
    
28.
Weil S, Vendola K, Zhou J, Bondy CA. Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab 1999;84:2951-6.  Back to cited text no. 28
    
29.
Messinis IE, Templeton AA. The importance of follicle-stimulating hormone increase for folliculogenesis. Hum Reprod 1990;5:153-6.  Back to cited text no. 29
    
30.
Lolis DE, Tsolas O, Messinis IE. The follicle-stimulating hormone threshold level for follicle maturation in superovulated cycles. Fertil Steril 1995;63:1272-7.  Back to cited text no. 30
    
31.
Porchet HC, le Cotonnec JY, Loumaye E. Clinical pharmacology of recombinant human follicle-stimulating hormone. III. Pharmacokinetic-pharmacodynamic modeling after repeated subcutaneous administration. Fertil Steril 1994;61:687-95.  Back to cited text no. 31
    
32.
Ben-Rafael Z, Levy T, Schoemaker J. Pharmacokinetics of follicle-stimulating hormone: Clinical significance. Fertil Steril 1995;63:689-700.  Back to cited text no. 32
    
33.
van Santbrink EJ, Hop WC, van Dessel TJ, de Jong FH, Fauser BC. Decremental follicle-stimulating hormone and dominant follicle development during the normal menstrual cycle. Fertil Steril 1995;64:37-43.  Back to cited text no. 33
    
34.
Balasch J, Miró F, Burzaco I, Casamitjana R, Civico S, Ballescá JL, et al. The role of luteinizing hormone in human follicle development and oocyte fertility: Evidence from in-vitro fertilization in a woman with long-standing hypogonadotrophic hypogonadism and using recombinant human follicle stimulating hormone. Hum Reprod 1995;10:1678-83.  Back to cited text no. 34
    
35.
Hull M, Corrigan E, Piazzi A, Loumaye E. Recombinant human luteinising hormone: An effective new gonadotropin preparation. Lancet 1994;344:334-5.  Back to cited text no. 35
    
36.
Howles CM. Luteinizing hormone supplementation in ART. In: Kovacs G, editor. How to Improve your ART Success Rate. UK: Published by Cambridge University Press; 2011. p. 99-104.  Back to cited text no. 36
    
37.
Balasch J, Fabregues F, Penarrubia J, Carmona F, Casamitjana R, Creus M, et al. Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor-responder IVF patients with normal basal concentrations of FSH. Hum Reprod 2006;21:1884-93.  Back to cited text no. 37
    
38.
Massin N, Cedrin-Durnerin I, Coussieu C, Galey-Fontaine J, Wolf JP, Hugues JN. Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique – A prospective, randomized, double-blind study. Hum Reprod 2006;21:1204-11.  Back to cited text no. 38
    
39.
Fábregues F, Peñarrubia J, Creus M, Manau D, Casals G, Carmona F, et al. Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: A randomized, clinical trial. Hum Reprod 2009;24:349-59.  Back to cited text no. 39
    
40.
Lee VC, Ledger W. Aromatase inhibitors for ovulation induction and ovarian stimulation. Clin Endocrinol (Oxf) 2011;74:537-46.  Back to cited text no. 40
    
41.
Durnerin CI, Erb K, Fleming R, Hillier H, Hillier SG, Howles CM, et al. Effects of recombinant LH treatment on folliculogenesis and responsiveness to FSH stimulation. Hum Reprod 2008;23:421-6.  Back to cited text no. 41
    
42.
Mendoza C, Ruiz-Requena E, Ortega E, Cremades N, Martinez F, Bernabeu R, et al. Follicular fluid markers of oocyte developmental potential. Hum Reprod 2002;17:1017-22.  Back to cited text no. 42
    
43.
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.  Back to cited text no. 43
    
44.
Olshansky SJ, Perls TT. New developments in the illegal provision of growth hormone for “anti-aging” and bodybuilding. JAMA 2008;299:2792-4.  Back to cited text no. 44
    
45.
Taylor E. Illegal human growth hormone markets. Issues in controlling online drug sales and advertising. J Leg Med 2008;29:237-53.  Back to cited text no. 45
    
46.
Liu H, Bravata DM, Olkin I, Friedlander A, Liu V, Roberts B, et al. Systematic review: The effects of growth hormone on athletic performance. Ann Intern Med 2008;148:747-58.  Back to cited text no. 46
    
47.
Sauter B. Growth hormone for “antiaging”. JAMA 2006;295:889.  Back to cited text no. 47
    
48.
Haouzi D, Assou S, Dechanet C, Anahory T, Dechaud H, De Vos J, et al. Controlled ovarian hyperstimulation for in vitro fertilization alters endometrial receptivity in humans: Protocol effects. Biol Reprod 2010;82:679-86.  Back to cited text no. 48
    
49.
Haouzi D, Assou S, Mahmoud K, Tondeur S, Rème T, Hedon B, et al. Gene expression profile of human endometrial receptivity: Comparison between natural and stimulated cycles for the same patients. Hum Reprod 2009;24:1436-45.  Back to cited text no. 49
    
50.
Zhu D, Zhang J, Cao S, Zhang J, Heng BC, Huang M, et al. Vitrified-warmed blastocyst transfer cycles yield higher pregnancy and implantation rates compared with fresh blastocyst transfer cycles – Time for a new embryo transfer strategy? Fertil Steril 2011;95:1691-5.  Back to cited text no. 50
    
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.  Back to cited text no. 51
    

 
  Authors Top


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).



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


This article has been cited by
1 The Benefits of Testosterone Therapy in Poor Ovarian Responders Undergoing In Vitro Fertilisation (IVF)
European Medical Journal. 2020;
[Pubmed] | [DOI]



 

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