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The re-growth of growth hormone in fertility treatment: A critical review
Abstract
Several clinical studies have recently been published documenting the possible role of adjuvant growth hormone treatment in in vitro fertilization. These studies have been performed on different groups of patients including poor ovarian responders, patients with polycystic ovary syndrome and with hypogonadotrophic-hypogonadism. The aim of this review is to examine relevant studies in the last 25 years, on the use of growth hormone in assisted conception and trace the train of events that has lead to the resurgence of interest in this subject.
... The difficulty with studying hGH supplementation in assisted reproduction is in part related to inconsistencies surrounding the appropriate patient population, dosage, timing and length of administration [24,[30][31][32][33]. Additionally, hGH is expensive and not FDA-approved for fertility treatment in the United States, limiting its widespread implementation and contributing to underpowered study designs [32,34,35]. ...
This study aims to compare endometrial growth before and after the addition of human growth hormone (hGH) in controlled ovarian hyperstimulation (COH) cycles. A 5-year retrospective cohort study of patients treated with hGH to improve oocyte development during COH cycles was conducted. Each patient’s cycle without hGH immediately preceding cycle(s) with hGH was used for patients to serve as their own controls. Primary outcome was absolute growth in endometrial thickness from pre-stimulation start to day of hCG trigger. Mixed-model regression analysis controlled for patient correlation over repeat cycles and potential confounders. 80 patients were included. Mean age was 39.7 years; mean BMI was 23.8 kg/m2. Majority of patients were nulliparous, non-smoking, and White or Asian. Most common diagnosis was diminished ovarian reserve. Endometrial growth was compared between 159 COH cycles with hGH and 80 COH control cycles; mean increase was 4.5 mm and 3.9 mm, respectively-an unadjusted difference of 0.6 mm (95% CI: 0.2–1.1, p = 0.01). After adjusting for demographic/clinical factors, hGH was associated with 0.9 mm greater endometrial growth (0.4–1.4, p < 0.01). Absolute increase in endometrial thickness was higher in COH cycles that included hGH. Further prospective studies in embryo transfer cycles are needed.
... Since LFOR is almost universally associated with low peripheral androgen levels (Gleicher et al., 2013), we, and others, have, utilized dehydroepiandrosterone (DHEA) and/or testosterone treatments in attempts to increase the cohort of antral follicles (Casson et al., 2000;Gleicher, 2005, 2006; Barad et al., 2007;Sellix and Sen, 2017). Growth hormone, through insulin growth factor-1 (IGF-1), has also been used as an adjuvant in ovarian stimulation in women with LFOR (Homburg et al., 2012;Dakhly et al., 2018). ...
Study question:
Does intraovarian injection of platelet-rich plasma (PRP) change ovarian function in patients with extremely low functional ovarian reserve (LFOR) who, otherwise, would likely only have a chance of pregnancy through third-party oocyte donation?
Summary answer:
No clinically significant effects of PRP treatment on ovarian function were observed over 1 year of follow-up.
What is known already:
Several investigators have reported improved responses to ovulation induction after treatment with PRP. However, previous published reports have involved, at most, only small case series. Whether PRP actually improves ovarian performance is, therefore, still unknown. PRP is nevertheless widely offered as an 'established' fertility treatment, often under the term 'ovarian rejuvenation'.
Study design size duration:
We are reporting a prospective cohort study of 80 consecutive patients at ages 28-54 with LFOR, defined by anti-Müllerian hormone <1.1 ng/ml, FSH >12 mIU/ml or at least one prior IVF cycle with ≤3 oocytes within 1 year. The women were followed for 1 year after an intraovarian PRP procedure.
Participants/materials setting methods:
PRP (1.5 ml) was injected into the cortex of ovaries with an average of 12 injections per ovary. Study participants were followed every 3 days for 2 weeks after PRP treatment with estradiol and FSH measurements and vaginal ultrasound to observe follicle growth and thereafter followed weekly. Beginning 1 month after their PRP treatment, participants underwent one or more cycles of ovarian stimulation for IVF. Outcome measures were endocrine response, and numbers of oocytes and embryos produced in response to a maximal gonadotropin stimulation before and after PRP treatment.
Main results and the role of chance:
In this study, women failed to demonstrate statistically significant outcome benefits from intraovarian PRP. However, two 40-year-old very poor-prognosis patients, with prior failed IVF cycles that never reached embryo transfer at other centers, achieved pregnancy, resulting in an ongoing pregnancy rate of 4.7% among patients who, following PRP, produced at least one oocyte (n = 42).
Limitations reasons for caution:
As an observational study of patients who performed poorly in past ovarian stimulation cycles, the improvement may be accounted for by regression to the mean. Similar considerations may also explain the occurrence of the two pregnancies.
Wider implications of the findings:
This study demonstrates that, even in extremely poor prognosis patients due to LFOR, sporadic pregnancies are possible. The study, however, does not allow for the conclusion that those pregnancies were the consequence of PRP treatments. A case series, indeed, does not allow for such conclusions, even if results are more suggestive than here. This registered study, therefore, must be viewed as a preliminary report, with further data expected from this study but also from two other prospectively randomized ongoing registered studies with more controlled patient selection.
Study funding/competing interests:
This work was supported by intramural funds from The Center for Human Reproduction and the not-for-profit research Foundation for Reproductive Medicine, both in New York, NY, USA. N.G. and D.H.B. are listed as co-inventors on several US patents. Some of these patents relate to pre-supplementation of hypo-androgenic infertile women with androgens, such as dehydroepiandrosterone and testosterone and, therefore, at least peripherally relate to the subject of this manuscript. They, as well as D.F.A., have also received research support, travel funds and speaker honoraria from several pharmaceutical and medical device companies, though none related to the here presented subject and manuscript. N.G. is a shareholder in Fertility Nutraceuticals and he and D.H.B. receive royalty payments from Fertility Nutraceuticals LLC. E.M. has no conflicts of interest to declare.
Trial registration number:
NCT04275700.
... The number of higher-quality embryos was improved by 0.86 but this improvement was not significant. Others have found that GH significantly elevates the number and quality of oocytes 36 . However, conclusions from these results should be drawn with caution because of the small sample size. ...
Oxidative stress (OS) is associated with poor oocyte quality and in vitro fertilization and embryo transfer (IVF-ET) outcomes for patients with polycystic ovary syndrome (PCOS). Growth hormone (GH) can function to reduce OS in some types of cells. Therefore, this prospective randomized study investigated whether GH can significantly improve OS and oocyte quality in women with PCOS. This study enrolled 109 and 50 patients with and without PCOS (controls), respectively. The patients with PCOS were randomly assigned to receive treatment with GH (PCOS-T) or not (PCOS-C). The primary outcome included markers of OS in serum and FF, and secondary outcomes were mitochondrial function in granulosa cells (GCs) and IVF-ET outcomes. The PCOS groups showed higher basal serum total oxidant status (TOS) and OS index (OSI) levels. The follicle fluid (FF) TOS and OSI and GC apoptosis rate were significantly higher, whereas the GC mitochondrial membrane potential (MMP) was significantly lower in the PCOS-C group than in the PCOS-T and non-PCOS control groups (P < 0.05). Significantly more oocytes were fertilised and cleavage stage embryos were produced in the PCOS-T group than in the PCOS-C group (P < 0.05). GH also improved the rates of implantation and clinical pregnancy, but not significantly (P > 0.05). This study showed that GH alleviated the TOS and OSI level in FF and improved GC mitochondrial dysfunction and oocyte quality in patients with PCOS.
Clinical Trial Registration Number: This project was prospectively registered on the Chinese Clinical Trial Registry on October 20, 2018. (ChiCTR1800019437) (https://www.chictr.org.cn/edit.aspx?pid=28663&htm=4).
... 16 Low levels of hGH have been observed in non-GHD adults, including elderly adults 16 and postmenopausal women. 17 Low hGH has also been observed in conditions including obesity, 18 fibromyalgia, 19,20 post-traumatic stress disorder, 21 female and male infertility, 22,23 impaired sleep, 24,25 and low muscle mass (e.g., sarcopenia). 26 Treatment with recombinant hGH is not indicated in non-GHD individuals, thus, there is a need for safe therapies that improve endogenous hGH secretion and symptoms associated with low hGH. ...
An oral test supplement increases serum human growth hormone (hGH) levels after acute administration in healthy adults. We investigated the mechanism for the increase in hGH and the effect of continued daily administration of the test supplement on measures of physical fitness and sleep efficiency. In Study 1, serum triiodothyronine (T3) was measured in samples from a prior placebo-controlled, double-blind study in which 16 healthy participants received both placebo and the test supplement in a crossover design; treatment order was randomized, and treatments were separated by a 1-week washout. In Study 2, physical fitness (VO2 max) was measured at baseline and after 2 weeks of daily administration of the test supplement (N = 12 healthy participants). Study 3 assessed daily sleep onset latency and time awake during 3 weeks of daily administration of the test supplement (N = 15 healthy participants). A fall from baseline in T3 was observed with placebo (-6.1 ± 8.5 ng/dL, P = .01). Of note, the change in T3 was smaller with the test supplement (-3.3 ± 10.7 ng/dL, P = not significant) but was not statistically different from placebo. Mean VO2 max increased by 6% from baseline after 2 weeks (P = .02). Sleep-onset latency and time awake during the night were reduced from baseline to week 3 by 22% and 65%, respectively (P = .01 and P = .02). The conservation of T3 levels suggests that the mechanism for increased hGH secretion by the test supplement is through somatostatin inhibition. Furthermore, pilot studies indicated that daily administration of the supplement improved physical fitness and sleep efficiency from baseline, effects consistent with increased endogenous hGH release. Clinical Trial Registration No. NCT02987868.
... The last point (#7) may be considered controversial with strong scepticism about GH use expressed by several prominent clinicians in the field [70,77,78] excepting when used for women with hypopituitarism. Such can be due to a range of anatomical causes such as empty Sella Turcica, pituitary adenomas, Rathke"s cyst/pouch, hypophysectomy and other intracranial trauma as well as medical conditions such as Sheehan"s syndrome. ...
... The last point (#7) may be considered controversial with strong skepticism about GH use expressed by several prominent clinicians in the field (70,77,78) excepting when used for women with hypopituitarism. Such can be due to a range of anatomical causes such as empty Sella Turcica, pituitary adenomas, Rathke's cyst/pouch, hypophysectomy, and other intracranial trauma as well as medical conditions such as Sheehan's syndrome. ...
IVF is currently regarded as a successful new technology with the number of IVF children currently well over 8 million worldwide. This has been achieved by an explosive plethora of facilities. However, from its earliest history, IVF has been beset by poor-prognosis on a treatment cycle basis, an aspect which has been a constant feature for the majority of treatments to this stage. The 2019 Australian and New Zealand Assisted Reproduction Database (ANZARD) report shows that IVF clinics have live birth productivity rates (from combined initiated fresh and frozen cycles) ranging from 9.3 to 33.2%. Over the past 40 years there have been a number of innovations which have steadily moved the success rates forward, but progress is held back by an intransigent group of women who can be classified as being poor-prognosis from one or more adverse factors, namely advanced age (>40 years), poor ovarian response (POR) to ovarian stimulation, inability to generate high quality blastocyst-stage embryos, recurrent implantation failure, or recurrent early pregnancy losses. A number of strategies are variously applied including the use of recombinant growth hormone (GH) adjuvant therapy. Our retrospective studies at PIVET over the past decade show a 6.2-fold chance of live birth for fresh cycle embryo transfers following GH injections of 1-1.5 IU daily given for 3-6 weeks in the lead-up to the trigger for ovum pickup. We have also recently reported the live birth rates from frozen embryo transfers utilizing those blastocyst embryos generated under GH influence and showed the live birth rate was 2.7-fold higher in a carefully matched poor-prognosis group. This experience has been compared to the total 42 GH studies reported since the year 2000, the majority matching those of PIVET with significant increases in both oocyte and embryo utilization rates but only ∼50% are followed by elevated live birth rates. We argue that this discrepancy relates to failure in addressing other causes of poor-prognosis along with the wastage of transferring more than a single embryo in the fresh cycle, when ANZARD data indicates a significantly higher chance of live birth from frozen embryo transfers.
... Initial reports on the use of GH in clinical practice come from cases of hypogonadotropic hypogonadism or panhypopituitarism (46). Subsequently, the use of GH has been expanded on different patient population, such as women with poor ovarian reserve, poor responders, or with poor oocyte quality due to advanced maternal age (25,47,48). In general, GH administration in the infertility clinic setting has focused on GH effects on oocyte, and the effect on endometrium has been largely overlooked. ...
Administration of growth hormone (GH) during ovarian stimulation has shown beneficial effects on in vitro fertilization (IVF) outcomes. It is generally believed that this improvement is due to the stimulating effect of GH on oocyte quality. However, studies are emerging that show possible positive effect of GH administration on endometrial receptivity, thus suggesting an additional potential benefit at the level of the uterus, especially among women with recurrent implantation failure, thin endometrium, and older normal responders. This review summarizes recent data on GH co-treatment effects on endometrium and endometrial receptivity among infertile women undergoing IVF, and proposes possible mechanisms of GH actions in the endometrium.
... 16 Low levels of hGH have been observed in non-GHD adults, including elderly adults 16 and postmenopausal women. 17 Low hGH has also been observed in conditions including obesity, 18 fibromyalgia, 19,20 post-traumatic stress disorder, 21 female and male infertility, 22,23 impaired sleep, 24,25 and low muscle mass (e.g., sarcopenia). 26 Treatment with recombinant hGH is not indicated in non-GHD individuals, thus, there is a need for safe therapies that improve endogenous hGH secretion and symptoms associated with low hGH. ...
SeroVital is an orally-administered amino acid supplement that promotes hGH secretion via suppression of somatostatin. We investigated if daily administration of the supplement would increase levels of endogenous insulin-like growth factor 1 (IGF-1), a primary mediator of the effects of hGH, and improve symptoms related to low-normal hGH production in a cohort of individuals being treated for fibromyalgia, a complicated condition associated with endocrine features including low or low-normal hGH. This open-label, single-arm study investigated the effects of 24 weeks of daily oral administration of the supplement in individuals with low-normal hGH production (between the 15th and 50th percentile for age-appropriate levels of IGF-1). The primary endpoint was the change from baseline to endpoint (Week 24) in serum IGF-1. Additional endpoints included the change in body weight, clinical symptoms (assessed with the Revised Fibromyalgia Impact Questionnaire [FIQR], range 0-100, and Perceived Stress Scale [PSS], range 0-40), fasting cardiometabolic markers, tolerability, and safety. Participants continued to receive standard care. The study enrolled 45 adults with mean baseline age (mean±SD) 67±11 years, 67% female, BMI 31±7 kg/m2, and IGF-1 107±28 ng/mL. High mean±SD baseline FIQR and PSS scores of 82±14 and 35±3, respectively, indicated poor to moderate control of fibromyalgia with standard care. All individuals completed 24 weeks of treatment. There was an increase in serum IGF-1 levels at Week 12 that was sustained to endpoint, resulting in a mean±SE Week 24 change of 32.1±2.8 ng/mL (paired t-test p<0.001). IGF binding protein-3 (IGFBP-3) levels were unchanged from baseline (p=ns), indicating no change in IGF-1 sensitivity. There was a steady reduction in body weight that resulted in Week 24 mean±SE change of -6.4±0.4 kg (p<0.001). The change from baseline in FIQR and PSS scores were -25.6±1.6 and -21.5±0.5, respectively (both p<0.001), indicating a substantial improvement. Statistically significant improvements from baseline were also observed for systolic and diastolic blood pressure, HbA1c, LDL and HDL cholesterol, and triglycerides (all p<0.001). The supplement was well tolerated; no adverse events were reported. In patients being treated for fibromyalgia with low-normal hGH production, daily addition of the hGH-enhancing supplement for 24 weeks produced an increase in IGF-1 with associated weight loss and improvements in cardiometabolic markers and clinical symptoms. Sustained augmentation of IGF-1 with the supplement may represent a unique method of improving clinical symptoms in individuals with low-normal hGH, including otherwise healthy adults exhibiting low-normal hGH production.This was an independent investigator-initiated study. Sierra Research Group provided some samples of the supplement.
With initial attempts of failed IVF, and also after miscarriages, it is quite common for women to assume and become convinced that there is a problem in the uterus or their body leading to the “rejection” of the embryos. This may be true for some women, but it is difficult to detect and predict which women this applies to. In fact, chromosomal errors in the embryos are probably the main underlying reason behind all reproductive failures, but uterine factors may have a role [1]. A recent analysis of more than 15, 000 high grade blastocysts showed 30-90% were aneuploid, increasing significantly with a woman’s age [2]. Sometimes pre-implantation genetic screening (PGS) is useful either prior to or in conjunction with adjuvant treatment to assess the necessity and limit the number of embryo transfer cycles and repeated use of adjuvant treatments.
How to Prepare the Egg and Embryo to Maximize IVF Success - edited by Gabor Kovacs January 2019
In a sequential crossover study of IVF conducted from 2002 to 2006, growth hormone (GH) supplementation was assessed in poor-prognosis patients, categorized on the basis of past failure to conceive (mean 3.05 cycles) due to low response to high-dose stimulation (<3 metaphase II oocytes) or poor-quality embryos. Pregnancy rates in both fresh and frozen transfer cycles and the total productivity rates (fresh and frozen pregnancies per egg collection) were compared. In all, 159 patients had 488 treatment cycles: 221 with GH and 241 without GH. These cycles were also compared with 1572 uncategorized cycles from the same period. GH co-treatment significantly improved the clinical pregnancy rate per fresh transfer (P<0.001) as well as per frozen-thawed embryo derived from GH cycles (P<0.05) creating a highly significant productivity rate (P<0.001). The effect was significant across all age groups, especially in younger patients, and was independent of stimulation modality or number of transfers. GH cycles resulted in significantly more babies delivered per transfer than non-GH cycles (20% versus 7%; P<0.001) although less than the uncategorized cycles (53%). The data uniquely show that the effect of GH is directed at oocyte and subsequent embryo quality.
Whether the addition of growth hormone (GH) can improve the probability of pregnancy in poor responders undergoing ovarian stimulation for in-vitro fertilization (IVF) has been examined to date by several underpowered studies, which have not provided solid conclusions.
A computerized literature search in MEDLINE, EMBASE, CENTRAL and randomized controlled trial (RCT) registries was performed independently by two reviewers, aiming to identify RCTs that evaluated the following research question: does GH addition increase the probability of pregnancy in poor responders undergoing ovarian stimulation with gonadotrophin releasing hormone (GnRH) analogues and gonadotrophins for IVF?
Six relevant RCTs were identified, including a total of 169 patients. GH addition significantly increased clinical pregnancy (rate difference: +16%, 95% CI: +4 to +28; fixed effects model) (number-needed-to-treat (NNT) = 6, 95% CI: 4-25) and live birth rates (rate difference: +17%, 95% CI: +5 to +30; fixed effects model) (NNT = 6; 95% CI: 3-20). Furthermore, GH addition was associated with a significantly higher proportion of patients reaching embryo transfer (rate difference: +22%, 95% CI: +7 to +36; fixed effects model).
The present meta-analysis provides evidence that GH addition increases the probability of clinical pregnancy and live birth in poor responders undergoing ovarian stimulation with GnRH analogues and gonadotrophins for IVF. However, the total number of patients analyzed is small and thus further RCTs are warranted to prove or disprove this finding.
Several growth factors augment the ovarian response to gonadotrophins and growth hormone is known to regulate the production of insulin-like growth factor-1. With this in mind, 20 women who had previously responded sub-optimally to standard ovarian stimulation regimens for in-vitro fertilization and embryo transfer (IVF-ET) were recruited into a randomized trial to study the effect of co-treatment with growth hormone (Norditropin, Novo Nordisk Gentofte A/S). Intramuscular injections of growth hormone (24 IU) or placebo were given on alternate days concurrently with the same daily dosage of gonadotrophin as administered in the patient's pretreatment cycle. Overall, there was no improvement in the ovarian response to the growth hormone-augmented regimen of stimulation although there was a tendency for the development of more follicles (P=0.06). When the results from the patients with ultrasound-diagnosed polycystic ovaries were analysed separately, however, more follicles developed (P=0.04), more oocytes were collected (P=0.03) and there was a trend towards higher urinary oestrogen production following growth hormone therapy. There was no improvement in the ovarian response in patients with normal ovaries. The treatment was not associated with any adverse effects. We conclude, therefore, that in a subgroup of patients who respond sub-optimally to standard ovarian stimulation regimens for IVF-ET and who have ultrasound-diagnosed polycystic ovaries, systemic growth hormone is an effective adjunctive therapy.
Objectives To explore the effect of recombinant, human GH on follicular development and oocyte retrieval after gonadotropin stimulation with the addition of GH or placebo to a standard IVF treatment regimen. Further, to investigate whether GH is a more effective adjuvant if the standard treatment regimen is preceded by GH injections. Design A randomized, double-blind, parallel, placebo-controlled study. Setting The IVF unit at university hospital. Patients Forty normally ovulating women, age 25 to 38years, with infertility because of tubal factors and being classified as "poor responders" with at least two previously performed and failed IVF attempts. Interventions Human, recombinant GH (Genotropin, Kabi Pharmacia, Uppsala, Sweden) or placebo (0.1IU/kg body weight per day) was given SC as pretreatment during down regulation with GnRH and during stimulation with hMG according to the randomized protocol. Main Outcome Measures Number of oocytes retrieved after stimulation, total amount of gonadotropin used, time required for stimulation, number of follicles developing, rate of fertilization, and cleavage in vitro. Further, the quality of embryos, development of the endometrium, rate of clinical pregnancy, and serum and follicular fluid (FF) concentrations of insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein-1 (IGFBP-1), and IGFBP-3 were estimated. Results The number of oocytes retrieved did not differ significantly between the groups, nor did the amount of hMG required for stimulation. The fertilization rate increased in patients who had received GH. Growth hormone caused a significant increase in serum and FF levels of IGF-I. An increase in serum IGFBP-3 could also be recorded in patients who had received GH. Conclusion Although certain beneficial effects were noted in GH-treated patients, the overall results did not support GH as a clinically useful adjuvant treatment.
We examined the effects of insulin-like growth factor (IGF)-I on follicular growth, oocyte maturation, and ovarian steroidogenesis and plasminogen activator (PA) activity in vitro, using a perfused rabbit ovary preparation in order to determine whether the follicle-stimulating effects of growth hormone (GH) are mediated by IGF-I. The addition of IGF-I to the perfusate stimulated follicular growth and the resumption of meiosis in follicular oocytes in a dose-dependent manner. There was no significant difference in the production of progesterone by perfused rabbit ovaries between IGF-I-treated and control ovaries, whereas IGF-I increased the production of estradiol (E2) by perfused rabbit ovaries in a dose-dependent manner. The concomitant addition of a monoclonal antibody recognizing the type I IGF receptor, alpha IR-3, to the perfusate significantly blocked IGF-I-stimulated follicular growth, oocyte maturation, and E2 production. Intrafollicular PA activity increased significantly 4 h after exposure to 10 or 100 ng/ml of IGF-I and reached maximal levels at 6 h. The percentage increase in follicle diameter at 6 h after exposure to IGF-I was significantly correlated with the intrafollicular PA activity. Treatment with GH resulted in a 2.7-fold increase in intrafollicular levels of IGF-I mRNA. The binding of [125I]-IGF-I to rabbit ovarian membrane preparations was inhibited by unlabeled IGF-I and IGF-II in a concentration-dependent manner. The relative affinity of the IGF-I receptor for IGF-I, IGF-II, and insulin was typical of type I binding (IGF-I > IGF-II > insulin). Affinity cross-linking of ovarian membranes with [125I]-IGF-I revealed a radiolabeled band corresponding to a molecular weight of 135,000, the alpha subunit of the type I IGF receptor. This band was totally displaced by IGF-I and alpha IR-3. It was concluded that IGF-I stimulated follicular development, E2 production, and oocyte maturation by interacting with its specific receptor located in rabbit ovarian membranes.
Recently, three meta-analyses have concluded that cotreatment with GH improves assisted reproduction outcome in poor controlled ovarian stimulation responders. Although generally GH supplements did not increase controlled ovarian stimulation response or number of oocytes, the supplements improved pregnancy and live-birth rates-thus speaking for an effect on oocyte quality.
To systematically review the literature to identify randomized controlled trials, which evaluate interventions aiming to improve the probability of pregnancy in poor responders undergoing in vitro fertilization (IVF).
Systematic review and meta-analysis.
University-based hospital.
None.
Pregnancy rate.
Twenty-two eligible randomized controlled trials were identified that evaluated in total 15 interventions to increase pregnancy rates in poor responders. Based on limited evidence, the only interventions that appear to increase the probability of pregnancy were the addition of GH to ovarian stimulation (odds ratio for live birth: 5.22, confidence interval: 95% 1.09-24.99) and the performance of embryo transfer on day 2 compared with day 3 (ongoing pregnancy rate: 27.7% vs. 16.3%, respectively; difference: +11.4, 95% confidence interval: +1.6 to +21.0).
Insufficient evidence exists to recommend most of the treatments proposed to improve pregnancy rates in poor responders. Currently, there is some evidence to suggest that addition of GH, as well as performing embryo transfer on day 2 versus day 3, appear to improve the probability of pregnancy.
In a preliminary, unpublished randomized study conducted in 2000 on 39 patients, including a placebo group, it was observed that the addition of growth hormone (GH) during ovarian stimulation in patients with poor-quality oocytes increased the pregnancy rate. However, the results were not statistically significant due to the small number of patients in each group. A protocol with 8 IU GH was tested in 291 patients with three or more previous failures of embryo transfer for no clearly identifiable reasons. The analysis was restricted to patients receiving either recombinant FSH or human menopausal gonadotrophin (HMG) (n = 245). They were compared retrospectively to all patients with three or more failures during the same period of time but stimulated only with recombinant FSH or HMG, without GH, in an observational study design. Co-stimulation with GH gave better results in terms of number of oocytes collected and embryos obtained. Pregnancy rate per retrieval was higher than in the control group (25.7% versus 18.2%, P < 0.01) and reached a level similar to the one observed in the study centre for the whole population. Ovarian stimulation associated with GH can be proposed for patients with a history of repeated assisted reproduction failures. An improvement of cytoplasmic competence is proposed as an explanation.
To determine the effect of growth hormone (GH) supplementation to a long gonadotropin-releasing hormone agonist (GnRH-a)/human menopausal gonadotropin (hMG) treatment protocol, on ovarian response, embryo quality, and clinical outcome in in vitro fertilization (IVF).
Growth hormone or placebo were administered in a prospective randomized double-blind manner.
Forty-two normal ovulatory, women who were 38 years of age or less with mechanical factor infertility and a normal male factor were selected for this study.
Gonadotropin-releasing hormone agonist, 0.5 mg/d, was initiated in the midluteal phase of the preceding cycle and continued until the day of human chorionic gonadotropin (hCG) administration. Ovulation induction with hMG was started 14 days after pituitary down regulation (17 beta-estradiol [E2] serum level less than 30 pg/mL). Growth hormone (12 IU/d) or placebo were administered on days 1, 3, 5, and 7 of hMG treatment.
Breaking the code at the completion of the study revealed that 20 women received GH and 22 placebo. The age and duration of infertility did not differ between the two groups. Follicular phase duration, hMG ampules used, serum E2, and number of follicles (greater than or equal to 14 mm) on day of hCG as well as number of oocytes and embryos achieved were similar in both groups. Embryo morphology and rate of cleavage were also similar. Insulin-like growth factor-I (IGF-I) serum levels did not change after pituitary down regulation and increased significantly both after GH/hMG and placebo/hMG ovulation induction treatment. Clinical pregnancy rate (PR) per embryo transfer and implantation rate were 40% versus 32% and 17.9% versus 11.3% in the GH and placebo groups, respectively, and were not statistically different.
In normo-ovulatory women undergoing ovulation induction for IVF, GH supplementation to hMG after GnRH-a pituitary down regulation does not seem to augment ovarian response or improve embryo quality. The effect of this regimen on actual PRs and implantation rates needs further clarification.