REVIEW published: 26 June 2019 doi: 10.3389/fendo.2019.00404 Growth Hormone and Reproduction: Lessons Learned From Animal Models and Clinical Trials Carlos Dosouto 1,2*† , Joaquim Calaf 1,2† , Ana Polo 1,2 , Thor Haahr 3,4 and Peter Humaidan 3,4 1 Obstetrics, Gynecology and Reproductive Medicine, Hospital de la Santa Creu I Sant Pau- Fundació Puigvert, Barcelona, Spain, 2 Faculty of Medicine, Autonomous University of Barcelona, Barcelona, Spain, 3 The Fertility Clinic Skive Regional Hospital, Skive, Denmark, 4 Faculty of Health, Aarhus University, Aarhus, Denmark Growth Hormone (GH) has been considered as a therapeutic option to increase the number of growing follicles during Assisted Reproductive Technology (ART) for more than 30 years. In this review the biological rationale for therapeutic GH usage is explained through evidence in animal models, aiming to put this into a clinical context. First, we explain the GH—Insulin like Growth Factor (IGF)-1—gonadal axis and its role in reproduction. Evidence suggests that GH can stimulate the secretion of IGF1 not only in the liver but also in the peripheral target structures, including the ovary. Moreover, IGF-1 can be secreted locally under the influence of stimuli other than GH. In the case Edited by: of the ovary, steroid hormones, gonadotropins or the combination of both seems to John Lui Yovich, be involved. Even more interesting, the ovary itself can secret GH locally and exert a Pivet Medical Center, Australia paracrine action modulating the intracellular signaling pathway of GH, i.e., not by the Reviewed by: Hakan Yarali, systemic pathway where GH binds to the extracellular domain of the GH receptor. Finally, Anatolia IVF Center, Turkey these aspects from animal models are put into clinical perspective by discussing results Marcos Horton, Pregna Medicina Reproductiva, and shortcomings of studies and meta-analyses in order to put forth the state-of-the-art Argentina rationale for therapeutic GH usage in modern ART. *Correspondence: Keywords: growth hormone, infertility, poor ovarian response, POSEIDON, IVF Carlos Dosouto cdosouto@fundacio-puigvert.es † Joint first authors INTRODUCTION Specialty section: GH is a monomeric protein secreted by the pituitary with a high molecular similarity to other This article was submitted to lactogenic hormones like prolactin and placental lactogen. In the anterior pituitary gland, the Reproduction, secretion by the somatotroph cell is regulated by both stimulatory peptides [e.g., Growth Hormone a section of the journal Releasing Hormone (GHRH)] and inhibitory (e.g., Somatostatin) peptides. The secretion takes Frontiers in Endocrinology place in a pulsatile way that combines short-term variability of spikes of irregular amplitudes Received: 20 March 2019 with a clear circadian increase, coinciding with the late non-Rapid Eye Movement (REM) Accepted: 06 June 2019 periods, probably mediated by dopamine related neurotransmitters (1, 2). This complicates the Published: 26 June 2019 determination of optimal plasma levels. The action of GH is exerted through its binding to the Citation: extracellular domain of a complex membrane receptor. In contrast to dimeric glycoproteins like Dosouto C, Calaf J, Polo A, Haahr T gonadotropins, two receptors are needed in order to establish a trimeric structure composed by and Humaidan P (2019) Growth two membrane receptors and the GH molecule. Thus, three recognition processes are needed for Hormone and Reproduction: Lessons Learned From Animal Models and an effective downstream activation: receptor-to-receptor and agonistic GH molecule to each of Clinical Trials. the receptors to form the activated GH trimeric complex. This complex relationship between the Front. Endocrinol. 10:404. hormone and the target organ makes the process of activation vulnerable to different mutations, doi: 10.3389/fendo.2019.00404 causing different downstream effects such as the clinical diversity in the different phenotypes of e.g., Frontiers in Endocrinology | www.frontiersin.org 1 June 2019 | Volume 10 | Article 404 Dosouto et al. Growth Hormone and Reproduction dwarfism (3, 4). The classic paradigm establishes that pituitary under the influence of gonadotropins, proving the importance of GH acts on its hepatic receptors and stimulates the secretion of IGF1 in the progression of cohorts from primordial and primary somatomedins or Insulin-like growth factors (IGFs): insulin like stage to recruitable secondary follicles and in the sensitivity growth factor 1 and 2 (IGF-1 and IGF-2). These are molecules to gonadotropins during the process of selection and follicular sharing near 50% homology with pro-insulin. However, IGF- growth. Interestingly, the histological observation shows an 1 and IGF-2 seem to have different roles. While IGF-1 is increase in primordial and primary follicles as compared to the considered the mediator of the classical biological actions on wild type animal and an absence of antral follicles. These findings growth, development and cellular proliferation, IGF-2 is relevant reinforce the idea of a crucial role for IGF in the process of in the regulation of perinatal development. The secretion of progression of the follicles from the non-gonadotropin sensitive IGFs is induced by GH mediated activation of single copy genes. to the gonadotropin sensitive stages. IGF mRNAs have been detected in several target tissues, and at Shiomi-Sugaya et al. observed that in an “in vitro” model the same time both IGF types exert a negative feedback at the of secondary follicles from mice isolated in gel media, the hypothalamic level maintaining basal steady levels of GH (1). growth rate of the follicles or their time to atresia correlate Both circulating and local bioavailability is regulated by high with IGF-1 mRNA expression (13). Also interesting is the affinity binding proteins which fine-tune their local action (5). relationship between IGF-1 mRNA and the presence of theca cells. Follicular progression was arrested by blocking IGF-1 production and restored by the co-culture with the cytokine, thus NEW EVIDENCE FROM ANIMAL MODELS confirming the importance of IGF-1 in follicular development. These observations suggest a peri-follicular microenvironment In the last decade the old paradigm described above has been where theca cells, beyond providing precursors for local estrogen challenged by new evidence obtained in genetically manipulated production, modulate follicular progression through paracrine research animals, introducing new elements of complexity to action of androgens and IGFs. be taken into account when interpreting the role of GH in A completely different approach to study GH role on follicular any peripheral structure, especially in the ovary. As reviewed dynamics is based in modifying GH secretion at the pituitary thoroughly by others (6), GH can stimulate the secretion of IGF- level (14). In GH df/df Ames dwarf mice GH pituitary secretion 1 not only in the liver but also in peripheral target structures (6). is practically abolished. In this context the pool of primordial Moreover, IGF-1 can be secreted locally under the influence of follicles is clearly increased as compared to N/df or wild type stimuli other than GH. In the case of the ovary, steroid hormones, animals. GH administration reverses this situation and decreases gonadotropins or the combination of both can be involved. primordial follicular count while increasing the number of antral Finally, the ovary itself can secret GH locally and exert a paracrine follicles. On the contrary, transgenic mice overexpressing GH action, modulating the intracellular signaling pathway of GH have a reduced number of primordial follicles as compared to and this occurs without binding to the extracellular domain of controls. It is relevant to note that, in the wild type animals, the membrane GH receptor. This is especially relevant since, the administration of GH diminishes the primordial follicular contrary to the pituitary secretion, the ovarian secretion of GH population but do not increase the number of antral structures, takes places in a regular, non-pulsatile, non-circadian pattern. probably due to a subsequent increased atresia rate. Taken In GHR knockout mice, circulating GH levels are high and together, these findings suggest that in the absence of GH, follicles IGF-1 levels are low (7). All studies on blocking or impairing remain in the primordial stage. the action of GH on its receptor report a delay in puberty, a significant reduction in litter size (a mean from 6, 7 in wild type animals to 2, 7 in transgenic) (8), and a corresponding delay in EVIDENCE FROM “HUMAN MODELS” the exhaustion of the follicular pool (3). However, the genetically modified animals are fertile and deliver small litters of healthy In humans the evaluation of GH role on reproduction can animals. The experimental data show that this decrease in litter be approached through two different models: GHRH or size is the consequence of a reduction in ovulation rate rather GH receptor mutations or combined pituitary hormone than problems related to implantation failure or early embryo deficiencies (CPHD). In the Itabaianinha County, in loss. Histological examination of the ovaries shows an increase Brazil, there is an ethnic group with high prevalence in primordial or primary follicles and a decrease in the number of a mutation of the gene encoding GHRHR gene, of healthy and growing antral or pre-ovulatory follicles (7–10). resulting in a severe reduction in GH signaling. Beyond It is difficult to establish to which extent this is the result of the phenotypic characteristics of GH deficiency, the abnormal GH signaling or its immediate downstream mediator, affected individuals have delayed puberty, but are fertile i.e., a decrease in local IGF-1 secretion. Interestingly, the negative mimicking what is found in animal models with GH effects seen in the abovementioned studies can be reverted by the deficiency (15). administration of IGF-1 (11). Similar clinical findings are observed in a group of A suitable model to clarify the specific role of IGF-1 is predominantly Sephardi Jewish with up to 29 mutations the IGF-gene knockout mouse (12). In these mice, the lack of the gene encoding for GHR (16). A cohort of seven of expression of IGFs results in dwarfism and infertility. The married women has been followed for their entire reproductive female mutated animals fail to ovulate either spontaneously or lives. Five of them have conceived 11 term pregnancies Frontiers in Endocrinology | www.frontiersin.org 2 June 2019 | Volume 10 | Article 404 Dosouto et al. Growth Hormone and Reproduction and 4 miscarriages. All pregnancies were spontaneous except FIRST CLINICAL EVIDENCE OF for one that was obtained by IVF. Six women reached THERAPEUTIC GH IN IVF menopause between 48 and 51 years. In a different model of childhood onset CHPD, Correa reports on five cases In the late eighties, a few case studies in patients undergoing from a single center. Pregnancy has been obtained in all COS for IVF and ovulation induction (OI) suggested that cases with controlled ovarian stimulation and GH –LT4 co- administration of GH improved the ovarian response to treatment (17). stimulation with gonadotropins (19–21). Later it was shown that GH treatment was associated with minor adverse reactions, mainly gastrointestinal symptoms, in ∼17% of cases (8/48) (22). SUMMARY: LESSONS LEARNED FROM The first reported mechanism by which GH would enhance FSH ANIMAL AND HUMAN MODELS action was by up-regulating the synthesis of IGF-1 in granulosa cells (23). Animal studies suggested that GH increased the intra- All experimental or clinical situations of early GH/IGF ovarian synthesis of the IGF-1 in vivo and in-vitro (24, 25) deprivation result in a delay in pubertal development with a and that this interaction was an important part of ovarian corresponding prolongation of reproductive life. Microscopically physiology in humans (26, 27). Addition of IGF-1 in granulosa there is a change in the composition of the follicular pools with cell cultures increased the intrinsic action of gonadotropins by a predominant population of primordial and primary follicles enhancing aromatase activity, estradiol (E2) and progesterone (P) and the absence or limited presence of more advanced stages production and LH receptor formation (27, 28) and was able to of follicles. This situation can be reverted with GH or IGF-1 stimulate follicular development and oocyte maturation (25). administration. IGF-1 has proven to be necessary for ovulation In 1990, a well-designed controlled clinical trial confirmed to occur while in the absence of GH follicular development, the synergistic effects of GH in patients undergoing IVF and ovulation, and pregnancy can take place. In these cases, however, stimulated with human menotropin gonadotropin (HMG) (21). the size of the litter is significantly decreased. All these findings However, another RCT with 20 suboptimal responder patients suggest a significant role of both systemic and local GH/IGF-1 concluded that there was no improvement in the ovarian regulation in the progress of follicles from non-gonadotropin to response by adding GH although there was a trend for more gonadotropin dependent status and also in improving follicular developing follicles (P = 0.06) (29). Interestingly, a sub-analysis development and oocyte maturation. Thus, it is biologically of this study in patients with polycystic ovaries (PCO) showed plausible that GH administration can play a positive role in a significant increase in the number of follicles developed (P = increasing the number of recruited follicles, especially in cases 0.04) and the number of oocytes retrieved (P = 0.03). The study with limited ovarian reserve. If the evidence from animal models did not report pregnancy rates and live birth rates (LBR) (29). can be directly translated into humans, the administration of Another study focusing on polycystic ovarian syndrome (PCOS) GH with the purpose of improving the oocyte yield should patients as a target for GH treatment found favorable responses in begin earlier than the stimulation with gonadotropins. In the terms of serum and follicular IGF-1 concentrations (30). Despite same line of thinking Gleicher and colleagues explore this not reporting conclusive clinical results, these and other early hypothesis, www.clinicaltrial.gov (NCT02179255), suggesting to studies reported that GH treatment seemed to promote ovarian initiate HGH at least 6 weeks prior to start of COS. steroidogenesis and follicular development (22). Figure 1 shows factors influencing the dynamics of follicular development. Activators such as GH and IFG-BP (Insulin Growth Factor Binding Protein) complexes, Insulin, androgens META-ANALYSES: A NEED FOR FURTHER and activin, might promote follicular growth, transition to RESEARCH antral stage or even follicular recruitment, either by acting as anti-apoptotic factors or enhancing follicular response to In 2003, a Cochrane review and meta-analysis concluded that gonadotropins. Inhibitors such as Anti Müllerian Hormone the use of GH in COS for IVF was in need of further research (AMH) are able to block initial follicle recruitment, transition (31). The meta-analysis covered studies with GH co-treatment to antral stage or even the gonadotropin-dependent recruitment. administered in varying dosages (4, 8, and 12 mg) and with Late follicular stages are predominantly influenced by endocrine intervention performed alongside stimulation start. There were factors such as gonadotropins: mainly FSH in the recruitment no significant differences in any outcome measure and at any of and selection of the leading follicle and LH at later stages and the dosages used. Following this meta-analysis, five subsequent last oocyte maturation and ovulation. Although there has been meta-analyses assessed the clinical use of GH as adjuvant in IVF. a clear differentiation between gonadotropin-independent and The first analysis reported an increase in the clinical pregnancy gonadotropin responsive/dependent stages, all the molecules rates (CPR) and LBR by the administration of GH during COS mentioned have been shown to take part not only at one level, with gonadotropins in PORs—an absolute increase in CPR by but in the entire process of folliculogenesis. Basic science studies 16% (95% CI: +4 to +28; fixed effects model) (number-needed- provide biologically plausible data for GH and IGF-1 as key to-treat = 6, 95% CI:4–25). Moreover, GH supplementation factors for an optimal follicle development. GH may play an was associated with a significantly higher proportion of patients activating role, either directly or indirectly, via for instance IGF-1 reaching embryo transfer (32). Despite this promising result, the in the transition from primordial follicles to late antral stages. total number of cases included in the meta-analysis was too small Frontiers in Endocrinology | www.frontiersin.org 3 June 2019 | Volume 10 | Article 404 Dosouto et al. Growth Hormone and Reproduction FIGURE 1 | Factors influencing dynamics of follicular pool development. Adapted from Gougeon (18) IGF-BP complexes (Insulin Growth Factor Binding Protein Complexes); GH (Growth Hormone); AMH (Anti Müllerian Hormone). Blue stripe shows follicular stages predominantly influenced by paracrine factors: activators such as GH and IFG-BP complexes, insulin, androgens and activin and AMH. Green stripe shows follicular stages predominantly influenced by endocrine factors such as gonadotropins. Although there has been so far a clear differentiation between gonadotropin-independent and gonadotropin responsive/dependent stages, all these molecules have shown to take part not only at one level, but in the whole folliculo-genesis. to reach robust evidence (only 169 patients in a total of 6 RCTs). co-administration of GH in IVF protocols in POR patients It is important to stress that from the 2003 Cochrane review to without increasing adverse events (OR 5.39, 95% CI 1.89–15.35). the meta-analysis by Kolibianakis by (32), only one well designed Notably, most of the studies included in these meta-analyses RCT was published in the literature, comparing the use of GH led to a potential bias in the results due to poor description of alone as an adjuvant to COS in PORs (33). The study involved the method of randomization. Moreover, there were significant 61 PORs patients, and the study group (n = 31) received daily differences in timing and dose of GH co-administration as well GH co-treatment (4 mg subcutaneously) mg from the first day of as high heterogeneity in the definition of POR. GnRHa down regulation (day 21 of the preceding cycle) until the In 2015, Yu et al. (38) performed an updated meta-analysis day of the ovulation trigger (OT). The control group (n = 30) reporting results in line with previous analyses. The results received the same protocol except for the GH co-administration. showed a significant improvement in terms of metaphase II A numerically higher CPR was achieved in the GH group (12/31) oocytes retrieved, number of 2PN obtained and number of as compared to the control group (6/30). However, this difference embryos available for transfer by GH supplementation in IVF did not reach statistical significance. Prior to that two Chinese patients. However, no difference was seen as regards CPR. studies were conducted in PORs and investigating the use of GH (34, 35). Both studies were only available in full-text in Chinese, hence, we did not include them in this review. THE SEARCH FOR THE MOST OPTIMAL Kyrou et al. (36) performed a meta-analysis of RCT‘s which STIMULATION PROTOCOL evaluated interventions aiming at increasing pregnancy rates in PORs. The only adjuvant treatment to standard stimulation A retrospective matched case–control study including 42 patients that appeared to increase the probability of live birth was the explored for the first time the effect of GH as an adjuvant addition of GH (OR 5.22, CI: 95% 1.09–24.99). Later, Duffy in a micro-dose GnRH agonist flare-up protocol. The study et al. (37) made a revised update of the Cochrane meta- group was treated with 3.33 mg GH daily subcutaneously (SC) analysis, including 10 studies with a total of 440 patients. Results for 14 days before starting COS (39). The authors did not demonstrated a statistically significant difference in LBR favoring find differences in any of the reported outcomes, although the Frontiers in Endocrinology | www.frontiersin.org 4 June 2019 | Volume 10 | Article 404 Dosouto et al. Growth Hormone and Reproduction small sample size and the retrospective character of the study (I 2 = 87 and 89%, respectively) (47). The latest meta-analysis necessitated a future RCT to draw firm conclusions. A RCT regarding the use of GH in COS was also published in 2017 including a total of 141 patients was subsequently performed (48). In that analyses all previous articles were included as in GnRH antagonist co-treated Bologna criteria POR patients well as data from the so-called LIGHT study (49). This was a (40). In this study, GH administration was initiated on day 6 multicenter, double-blind, placebo-controlled trial performed in of hMG stimulation in a daily dose of 2.5 mg SC until the day 10 centers throughout Australia and New Zealand. Authors did of HCG trigger. The study group had significantly fewer days not include Bologna or POSEIDON criteria for POR. A GH of stimulation, more oocytes retrieved and better fertilization dose of 12IU was administered from the first day of stimulation rates, albeit the authors did not find significant differences in in the intervention group. After 4 years of enrollment, the CPR per cycle and LBR per cycle. These results were similar to study was stopped prematurely, reporting only 130 patients those previously published in the first RCT using GH during randomized. The number of patients reaching an oocyte retrieval GnRH antagonist co-treatment (41). In 2015, an open label per randomized cycle was significantly higher in the GH group four arm randomized study including a total of 287 POR (62/65 [95.4%] vs. 51/65 [78.5%], OR 5.67, 95% CI 1.54–20.80), patients aligned with the ESHRE Bologna criteria aimed at however, no differences were reported in the LBR (9/62, [14.5%] comparing 4 different stimulation protocols (42). All groups were vs. 7/51, [13.7%], risk difference 0.8%, 95% CI −12.1 to 13.7%; administered GH on day 6 of hMG stimulation in a daily dose OR 1.07, 95% CI 0.37–3.10). Unlike other studies, no statistical of 2.5 mg SC. Patients were randomly allocated to either a long differences were reported between groups regarding the mean or short GnRH agonist protocol, mini-flare or GnRH antagonist number of oocytes retrieved (5 vs. 4, rate ratio 1.25, 95% CI 0.95– protocol. The long protocol was superior regarding the number 1.66) and the chance of reaching embryo transfer (53/61 [86.9%] of oocytes retrieved and fertilization rate, although no differences vs. 42/51 [82.4%], OR 1.42, 95% CI 0.50–4.00). No differences were seen in CPR. More recently, Dakhly et al. explored GH in embryo quality were found between groups. Results from this adjuvant treatment in the long agonist protocol in a prospective study should be interpreted with caution, as it was underpowered randomized study with 240 patients (43). The intervention group due to the few number of patients included. received adjuvant GH co-treatment 2.5 mg s.c (7.5 IU) from day 21 of the previous cycle along with GnRHa, until the day of CONCLUSIONS HCG trigger. Authors found statistically significant differences in terms of number of oocytes collected in favor of GH [(5.4 ± The use of GH to enhance follicular response to gonadotropin 1.7) vs. 4.3 ± 2.1], but they failed to show statistical differences stimulation has biological plausibility, as shown in animal in LBR in both fresh (17.5 vs. 14.1%) and cumulative frozen and human models. The GH/IGF system plays a pivotal role embryo transfer cycles (18.3 vs. 14.7%) (43). However, this study in the regulation of follicular dynamics. Any experimental was criticized for mainly two shortcomings (44): (i) A mean manipulation reducing the exposure to either GH or IGF lead to of 2.4 and 1.6 embryos were transferred in the study group an imbalance between the primordial gonadotropin independent and the control group, respectively, in the fresh cycle, yielding and gonadotropin sensitive follicular pools and a subsequent the results difficult to interpret with today’s standard of using decrease in the size of the litter. However, to date, although single embryo transfer and (ii) the luteal phase support with a higher number of oocytes has been consistently reported micronized progesterone pessaries 400 mg twice daily seemed researchers failed to show benefits in terms of LBR with the use suboptimal for the POR patients and the most optimal approach of adjuvant GH. The use of GH is definitely “unfinished business” would be with a combination of HCG injections and micronized and future trials with bigger sample size need to be more specific progesterone pessaries 400 mg three times daily as described by as regards inclusion criteria, treatment protocol and GH dose to Yovich previously (45) or other methods of ensuring optimal draw firm conclusions. Until then, it seems that some clinicians mid-luteal serum P levels (46). would use GH as adjuvant whereas many would not. MOST RECENT META-ANALYSES AUTHOR CONTRIBUTIONS Recently, Li et al. (47) performed a meta-analysis including 11 The style and concept were developed by CD, JC, TH, and RCT’s with a total of 663 patients. A pooled result, using fixed- PH. CD and JC produced the figure. All authors contributed effects model showed that the CPR and LBR per transfer were to writing the manuscript, contributed with critical review, significantly higher in the GH group (RR 1.65, 95% CI 1.23– discussions regarding the final content of this review, and 2.22; p < 0.001 and RR 1.73, 95% CI 1.25–2.40; P < 0.001, accepted the submission of this manuscript for publication. respectively). Moreover, the cycle cancellation rate (RR 0.65, 95% CI 0.45–0.94; P = 0.02) was significantly lower in GH co-treated ACKNOWLEDGMENTS cycles. No significant difference was seen in implantation rate (RR 1.05, 95% CI 0.56–1.99; P = 0.87). 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The addition of growth hormone adjuvant therapy to the long down Ferring as well as honoraria for lectures from MSD, Merck, Gedeon-Richter, regulation protocol in poor responders undergoing in vitro fertilization: Theramex, and IBSA. PH is a co-founder in the POSEIDON group. randomized control trial. Eur J Obstet Gynecol Reprod Biol. (2018) 228:161–5. doi: 10.1016/j.ejogrb.2018.06.035 The remaining authors declare that the research was conducted in the absence of 44. Yovich JL, Ye Y, Keane KN. Growth hormone adjuvant trial for poor any commercial or financial relationships that could be construed as a potential responders undergoing IVF. Eur J Obstet Gynecol Reprod Biol. (2019) 236:249. conflict of interest. doi: 10.1016/j.ejogrb.2019.01.026 45. Yovich JL, Alsbjerg B, Conceicao JL, Hinchliffe PM, Keane KN. PIVET Copyright © 2019 Dosouto, Calaf, Polo, Haahr and Humaidan. This is an open- rFSH dosing algorithms for individualized controlled ovarian stimulation access article distributed under the terms of the Creative Commons Attribution enables optimized pregnancy productivity rates and avoidance of ovarian License (CC BY). The use, distribution or reproduction in other forums is permitted, hyperstimulation syndrome. Drug Des Devel Ther. (2016) 10:2561–73. provided the original author(s) and the copyright owner(s) are credited and that the doi: 10.2147/DDDT.S104104 original publication in this journal is cited, in accordance with accepted academic 46. Thomsen LH, Kesmodel US, Erb K, Bungum L, Pedersen practice. No use, distribution or reproduction is permitted which does not comply D, Hauge B, et al. The impact of luteal serum progesterone with these terms. Frontiers in Endocrinology | www.frontiersin.org 7 June 2019 | Volume 10 | Article 404