SYSTEMATIC REVIEW published: 26 May 2020 doi: 10.3389/fpsyt.2020.00479 Women Undergoing Hormonal Treatments for Infertility: A Systematic Review on Psychopathology and Newly Diagnosed Mood and Psychotic Disorders Alexandre González-Rodrı́guez 1*, Jesús Cobo 1, Virginia Soria 2, Judith Usall 3, Clemente Garcia-Rizo 4, Miquel Bioque 4, José Antonio Monreal 1, on behalf of PNECAT Group and Javier Labad 1 1 Department of Mental Health, Parc Tauli Hospital Universitari, Institut d’Investigació i Innovació Parc Tauli (I3PT), Edited by: Autonomous University of Barcelona (UAB), Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM), Grazia Rutigliano, Sabadell, Spain, 2 Department of Psychiatry, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), University of Pisa, Italy Department of Clinical Sciences, University of Barcelona (UB), Centro de Investigación Biomédica en Red en Salud Mental Reviewed by: (CIBERSAM), Hospitalet de Llobregat, Barcelona, Spain, 3 Mental Health Services, Parc Sanitari Sant Joan de Déu, Sant Boi Alexis E. Cullen, de Llobregat, Spain, 4 Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic de Barcelona, Institut King’s College London, d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red en Salud Mental United Kingdom (CIBERSAM), Department of Medicine, University of Barcelona, Barcelona, Spain Ivana Zivoder, University North, Croatia Maarten Van Den Buuse, Background: The association between infertility treatments and mental disorders has La Trobe University, Australia been poorly addressed. This work aims to review current evidence on the *Correspondence: psychopathological effects of hormonal treatments used for infertility on women and the Alexandre González-Rodrı´guez occurrence of newly diagnosed mood and psychotic disorders. agonzalezro@tauli.cat Methods: A systematic review was performed by searching PubMed and clinicaltrials.gov Specialty section: databases from inception until September 2019. Clinical trials on hormone treatments for This article was submitted to Schizophrenia, infertility in patients with mood or psychotic disorders, as well as those evaluating the a section of the journal onset of symptoms, were included. Selected studies were published in English, Spanish, Frontiers in Psychiatry and Dutch language peer-reviewed journals. Preferred Reporting Items for Systematic Received: 11 March 2020 Reviews and Meta-Analyses (PRISMA) guidelines were followed. Observational studies Accepted: 11 May 2020 Published: 26 May 2020 and case reports were excluded. Effect sizes for changes in depressive symptoms were Citation: calculated with Hedges’g and Cohen’s d confidence intervals. A meta-analysis was not González-Rodrı´guez A, Cobo J, performed due to the heterogeneity of hormonal compounds in protocols. Soria V, Usall J, Garcia-Rizo C, Bioque M, Monreal JA and Labad J Results: From 1,281 retrieved records, nine trials were included; all of them were (2020) Women Undergoing Hormonal conducted in non-clinical populations. Four trials compared Gonadotropin-releasing Treatments for Infertility: A Systematic Review on Psychopathology and hormone (GnRH) agonists and GnRH antagonists, showing a better mood profile for Newly Diagnosed Mood and hormonal protocols including antagonists in one trial. Two trials compared protocols using Psychotic Disorders. Front. Psychiatry 11:479. GnRH agonists/antagonists versus natural cycle protocols (without gonadotropin doi: 10.3389/fpsyt.2020.00479 stimulation), with a better mood profile (less depressive symptoms) in those protocols Frontiers in Psychiatry | www.frontiersin.org 1 May 2020 | Volume 11 | Article 479 González-Rodrı´guez et al. Psychopathology and Infertility Treatment without gonadotropin stimulation. Other studies compared long and short protocols of GnRH agonists (no differences); two GnRH agonists, buserelin, and goserelin (no differences); and two patterns of clomiphene vs placebo administration (no differences). None of the selected studies investigated the risk of relapse in women with a previous diagnosis of depressive or psychotic disorders. When exploring pre-post changes in depressive symptoms, effect sizes suggested mild mood worsenings for most protocols (effect sizes ≤ -0.4), with the following pattern (worse to better): GnRH agonist > GnRH antagonist > no gonadotropin stimulation. Conclusions: This is the first systematic review exploring the psychopathological effects of hormonal infertility treatments. Our study suggests that protocols without gonadotropin stimulation show a better mood profile when compared to those using GnRH antagonists or GnRH agonists. Future studies need to include patients with major mood and psychotic disorders. Keywords: infertility, sex hormones, fertility treatments, psychosis, affective INTRODUCTION controlled ovarian stimulation. These molecules are factors that can be associated with psychopathological changes in Women with fertility problems have been extensively found to healthy women and women with previous mental disorders (9). suffer from psychological burden and may experience this Many biological compounds have been developed for clinical situation as very stressful (1). The relationship between ovulation induction in IVF, with the main aim of obtaining assisted reproductive technologies (ARTs) and mental distress is more oocytes (13), including clomiphene citrate, aromatase complex, and it calls for a careful examination of the direction of inhibitors, gonadotrophins, and gonadotropin-releasing the effects between both variables (2–4). hormone (GnRH) analogues (9). Clomiphene citrate blocks ART treatments may increase mental distress in women oestrogen receptors and increases follicle-stimulating hormone undergoing these therapeutic options (1). Mental health (FSH) levels. Aromatase inhibitors block the conversion of consequences may be partially explained by psychological androgens to oestrogens. Gonadotrophins include recombinant factors, such as neuroticism, as well as by biological factors FSH and luteinizing hormone (LH), and GnRH analogues derived from the biochemical nature of treatment compounds (3). include agonists and antagonists. When focusing on reproductive medicine, it seems to be Conventional controlled ovarian stimulation protocols crucial to determine whether a woman is infertile (5). Medical include the administration of gonadotropin-releasing hormone history (e.g., health history, the use of other medications); (GnRH) agonists with the main aim of the desensitization of the physical examination; blood tests including assessments of pituitary gland through the suppression of the release of both hormone levels; and ultrasonography exploring the ovaries, pituitary follicle-stimulating hormone (FSH) and luteinizing uterus and Fallopian tubes appear to be mandatory (5, 6). In hormone (LH) (13). This technique has been successfully some cases, infertility in women might be secondary to an associated with IVF; however, several adverse effects have also ovulation problem or an obstruction of the Fallopian tubes (7). been described, such as mood disturbances (3). More recently, However, in 5%–15% of cases, all tests and physical examinations GnRH antagonist protocols have been found to be an alternative are normal, and specific causes cannot be determined (8). for ovarian stimulation. They seem to show lower rates of Once the cause of infertility is found, all potential options for ovarian hyperstimulation syndrome and may reduce the length treatment should be considered (9). Briefly, four main types of of ovulatory stimuli compared with other ovulation induction infertility treatment are available: gamete intrafallopian transfer protocols (14). GnRH antagonist protocols are based on the daily (GIFT) and zygote intrafallopian transfer (ZIFT), intrauterine administration of recombinant follicle stimulating hormone (r- insemination (IUI), and in vitro fertilization (IVF) techniques FSH) analogue to start ovarian stimulation (2–3 cycle days). (10). IUI is a fertility treatment based on placing sperm directly Some studies have found GnRH protocols to have higher rates of into the uterus while the woman is ovulating (11). IVF is an ART pregnancies than treatment with clomiphene or aromatase process based on controlled ovarian stimulation, egg retrieval from inhibitors (13). More recently, a short GnRH antagonist women’s ovaries and the fertilization of these eggs with sperm in protocol has been recommended for younger women the laboratory (11). Finally, the embryo is placed in the woman’s undergoing their first ART cycle (14). uterus. GIFT and ZIFT refer to the collection and placement of Nevertheless, sex hormones have been found to regulate gametes or zygotes, respectively, into the Fallopian tube (12). mood and may play an important role on the pathophysiology Regarding IVF techniques, we will focus on the use of of affective disorders as well as schizophrenia and other psychotic biological compounds, mainly hormones, aiming to achieve disorders (15). Rubinow and Schmidt proposed several models to Frontiers in Psychiatry | www.frontiersin.org 2 May 2020 | Volume 11 | Article 479 González-Rodrı´guez et al. Psychopathology and Infertility Treatment explain how sex may influence brain function by means of METHODS hormonal effects and how the regulation of affect may be sex dependent (16). These investigations have also been conducted Search Strategy in patients with psychotic disorders. If the response to stress may A systematic computerized search was performed by focusing on be dysregulated in psychosis, Goldstein and co-workers (17) trials evaluating the effect of hormone treatments for infertility in reported that the interplay between steroid hormones and neural major depression, bipolar disorder, schizophrenia, and other activity may be sex dependent in psychosis, particularly for brain psychotic disorders. PubMed database and ClinicalTrials.gov functions implicating the prefrontal cortex (17, 18). were searched from inception until September 2019 in keeping In the particular case of GnRH agonists, it should be noted with the Preferred Reporting Items for Systematic Reviews and that they combine hormonal control of the cycle by means of a Meta-analyses (PRISMA) guidelines (26). Electronic search was hypoestrogenism state. This short induced-hormonal state may also completed by revising all references of including studies for determine subsequent mental health consequences that may be potential papers to be included. partially explained through the hypothalamic-pituitary-gonadal The following search terms were used: (clomiphene OR GnRH axis (19). Hormonal changes and withdrawal of oestrogens may OR letrozole OR vorozole OR anastrozole OR aromatase determine an increased vulnerability to depression in women as inhibitors OR FSH OR LH OR r-FSH OR r-LH OR in vitro well as a poorer prognosis (worsening of psychotic symptoms, fertilization OR IVF OR ICSI OR intracytoplasmic sperm injection greater risk of relapse and higher needs of antipsychotic dosages) OR ovarian stimulation OR controlled ovarian hyperstimulation) in female patients with schizophrenia (20, 21). Therefore, those AND (psychiatric OR psychopathology OR psychopathological fertility treatments that induce hypoestrogenism may have a OR relapse OR recurrence OR depression OR bipolar OR mania negative effect on depressive or psychotic symptoms. OR psychosis OR schizophrenia) AND trial. Although some studies have addressed the effects of sex steroids in brain functions in individuals with and without Inclusion Criteria mental illnesses (15–18), no previous systematic reviews have Studies that met the following inclusion criteria were considered: explored the effects of infertility hormonal treatments on a) trials focused on evaluating the effect of hormonal treatment for psychopathology in women. The vast majority of the studies infertility on women; b) studies that evaluated psychopathological have investigated pregnancy outcomes or other somatic effects of infertility treatments on women without a diagnosis of concerns, and psychopathological symptoms have been mental disorders (newly diagnosed mental disorder) or in women widely neglected. with a previous mental disorder (major depression, bipolar Several observational studies have investigated the prevalence disorder, schizophrenia and other psychotic disorders); rates for psychiatric disorders in women undergoing fertility c) published trials in peer-reviewed journals or registered in treatments (22). The authors found a prevalence of mood clinicaltrials.gov; d) articles written in English, Spanish or Dutch disorders around 26% in women, highlighting that major language; and e) studies that assessed the effectiveness of hormone depression was the most common diagnosis. In contrast with compounds for the treatment of infertility. these findings, Salih Joelsson et al. (23) compared depressive The exclusion criteria were as follows: a) naturalistic studies symptoms in pregnant and non-pregnant women, and and case reports, b) studies assessing the effect of hormone pregnant women receiving fertility treatment (23). Pregnant compounds administered for uses other than the treatment of women did not differ in depressive symptoms compared to the infertility, and c) studies exploring the effectiveness of hormone other two groups, suggesting a lack of negative effect of fertility drugs to treat mental disorders. treatments on psychopathological symptoms. More recently, Freeman et al. (24) carried out a prospective observational Data Collection and Extraction study in women with a previous history of unipolar or bipolar Titles and abstracts of studies identified in the initial searches depression undergoing fertility treatment (24). They concluded were screened independently by two review authors (AG-R and that maintenance of psychotropic medication was not sufficient JC). The same authors extracted data independently. Any for avoiding affective recurrences. With regard to schizophrenia disagreements or discrepancies between them were resolved by and other psychoses, a national register study compared the consensus and were explored with a third additional reviewer. success rates of fertility in women with and without psychotic Full-text documents were also reviewed. From the initially disorders (25), although exacerbation of psychotic symptoms selected articles, those that did not meet our inclusion criteria was not investigated. or met any exclusion criterion were excluded. The last search was In brief, findings from cohort and observational studies seem conducted on 29th October 2019. The PICO method for the to be contradictory and inconclusive. Therefore, we aimed to systematic review is detailed in Table S1. systematically review current evidence on the psychopathological effects of hormonal treatments for infertility on women and the Risk of Bias influence of these treatments on the occurrence of newly The risk of bias was evaluated using the Cochrane risk of bias tool. diagnosed mental disorders. We focused mainly on Studies were classified into three categories attending to their investigations concerning women with mood disorders and quality: good, fair, and poor. A meta-analysis was not performed psychotic disorders. due to the heterogeneity of the hormonal treatment protocols. Frontiers in Psychiatry | www.frontiersin.org 3 May 2020 | Volume 11 | Article 479 González-Rodrı´guez et al. Psychopathology and Infertility Treatment Effect Sizes for Changes in Depressive be known for calculating the confidence intervals in effect sizes Symptoms (30). As these correlations were not reported in studies, we For those clinical trials that included information on depressive calculated different confidence intervals using different symptoms at baseline and after the hormonal treatment for estimated correlations (r = 0, r = 0.25, r = 0.5, r = 0.75). The infertility, effect sizes were calculated. Hedges’ g was used as a confidence intervals calculated with a correlation of 0.5 will be measure of the effect size for changes in depressive symptoms included in a table in the article and the confidence intervals after the hormonal protocol using an on-line calculator that calculated with different correlations (sensitivity analyses) will be allows the calculation of the effect size for paired samples tests included in the supplementary material (Table S3). (https://effect-size-calculator.herokuapp.com/#paired-samples- Hedges’g and Cohen’s d are effect size measures that indicate t-test). Another effect size measure considered in the systematic the standardized difference between two means. It is assumed that review was confidence intervals (lower and upper limits) using 0.2 can be considered a “small” effect size, 0.5 represents a Cohen’s d. These measures were calculated using pre-post scores “medium” effect size and 0.8 a “large” effect size (31). In our (depressive symptoms) and standard deviation measures of all systematic review, as effect sizes represent changes in depressive studies with available data. If data were available as the median symptoms, positive effect sizes would imply mood improvement (interquartile range), the mean and SD were estimated as (reduction in depressive scores after hormonal treatment) whereas described previously (27). In a few cases in which data were negative effect sizes would indicate mood worsening. Effect sizes only available in figures, we extracted this information from closer to zero correspond to hormonal treatments that were figures using the same procedure explained in a recent systematic relatively “neutral” in terms of changing the mood status. review (28). Previous studies suggest that data extraction from figures shows high precision and seems to be a useful option to perform a meta-analysis when randomized clinical trials publish RESULTS figures as the only source of outcome data (29). Because the correlation between pre- and post-scores is A total of 1,281 abstracts were identified, 1,257 in PubMed and required to impute the standard deviation within groups from 24 through other sources (www.clinicaltrials.gov). Further details the standard deviation of the difference, this correlation needs to of the screening and selection process are described in Figure 1. FIGURE 1 | Flowchart for studies inclusion. Frontiers in Psychiatry | www.frontiersin.org 4 May 2020 | Volume 11 | Article 479 González-Rodrı´guez et al. Psychopathology and Infertility Treatment Published Articles Reporting gonadotropin (hCG). NC-IVF patients received no stimulation at Psychopathological Effects of Hormonal all or very low dosages of clomiphene citrate from day 6 or 7 of the Treatments Used for Infertility menstrual cycle until the day of ovulation induction with hCG. Eight trials investigated the effects of hormones used in women Depressive symptoms were evaluated in all women by means of undergoing fertility treatments (2, 3, 32–37). All of them evaluated the Center for Epidemiologic Studies Depression Scale. The the effect of GnRH antagonists or GnRH agonists on the occurrence authors found that patients who were given gonadotropin of newly diagnosed depressive symptoms in women (Tables 1, 2 stimulation showed higher rates of depression than women who and 3). None of them explored the effects of ART on women with a were not given gonadotropin stimulation. previous history of affective or psychotic disorders or the occurrence Greco et al. (33) included 236 women who underwent of psychotic or manic symptoms in women without a previous infertility treatment in a prospective controlled randomized diagnosis of mental disorder. trial (33). Two methods of endometrial preparation for Haemmerli-Keller et al. (32) carried out a non-randomized trial blastocyst transfer were applied: modified natural cycle and comparing women undergoing IVF with (cIVF) and without artificial cycle. Frozen-thawed single euploid blastocyst transfer gonadotropin stimulation (NC-IVF) (32). In the cIVF arm by means of a modified natural cycle was applied to 118 women. (gonadotropin stimulation), human menopausal gonadotropin The hormonal protocol for this treatment arm did not include (HMG) was initiated between days 3 and 5 of the menstrual gonadotropin stimulation and final oocyte maturation was cycle, and GnRH antagonists were first administered induced with hCG. One hundred 18 women were included in subcutaneously between days 6 and 7 of the menstrual cycle and the artificial cycle arm. The hormonal protocol for this treatment continued until ovulation induction with urinary human chorionic arm consisted of the administration of a GnRH agonist TABLE 1 | Main characteristics of published clinical trials reporting psychopathological complications with hormonal treatments for infertility (n=8). Author and year of Sample Country Mean age (SD) or Inclusion criteria Treatment (main arm and control group) publication size (n) Median [IQR] Haemmerli Keller 119 Switzerland NC-IVF: 34.0 (7.2) Women between 18 and 42 years Non-randomized trial: et al. (32) women c-IVF: 34.9 (4.5) with indication of IVF c-IVF or NC- a) c-IVF (IVF with HMG and GnRH antagonists) (n=62) IVF depending on medical indication b) NC-IVF (IVF without gonadotropin stimulation) (n=57) and women’s wishes Greco et al. (33) 236 Italy Modified-NC: 35.2 Women with indication of IVF at their Randomized controlled trial, method of preparation, women (3.6) first IVF cycle blastocyst transfer: AC: 35.5 (3.8) a) modified natural cycle (n=118) b) artificial protocol (n=118), GnRH agonist combined with oestradiol valerate Mamata et al. (34) 692 India GnRH antagonists: Women from 12 sites in India, aged Non-randomized trial: women 30.6 (3.83) 18- 45 years undergoing for first a) Group A - GnRH antagonist (n=232) GnRH agonists: 30.7 cycle of IVF/ICSI b) Group B - GnRH agonist (n=460) (4.21) Stenbæk et al. (3) 83 Denmark GnRH antagonist: 31.2 Women undergoing first infertility Randomized trial: women, [35.5-28.4] treatment cycle of IVF or ICSI a) GnRH antagonist (n=42): daily injections with r-FSH GnRH agonist: 36.4 b) GnRH agonist (n=41) [37.6-32.7] Bloch et al. (2) 108 Israel Total sample: 31.8 Women admitted, period 2006-2007, Prospective randomized trial: women (5.4) first or second IVF cycle Age < 42 a) Short protocol (GnRH agonist triptorelin plus daily r- years No endometriosis No FSH (n=60) b) Long protocol (GnRH agonist triptorelin psychopharmacological treatment for 14 days, followed by r-FSH (n=48) de Klerk et al. (36) 391 The Mild strategy: 33.0 Women who planned IVF, Randomized controlled two-center trial: women Netherlands (3.0) randomization into one protocol No a) Mild ovarian stimulation (GnRH antagonist co- Standard strategy: previous history of unsuccessful IVF treatment) and single embryo transfer (n=197) 32.8 (3.3) b) Standard GnRH agonist long-protocol ovarian stimulation with double embryo transfer (n=194) Heijnen et al. (35) 404 The Mild strategy: 32.9 Women who planned IVF or Randomized non-inferiority trial: women Netherlands (3.1) intracytoplasmatic sperm injection a) GnRH antagonist combined with single embryo Standard strategy: with no previous IVF history transfer (n=205) 32.8 (3.2) b) GnRH agonist long protocol and transfer of two embryos (n=199) Tapanainen et al. 100 Finland Goserelin: 33.6 (4.0) Women who planned IVF Randomized trial: (37) women Buserelin: 33.6 (3.8) a) Long-acting s.c. goserelin (LHRH agonist) (n=49) b) Buserelin acetate i.n. (LHRH agonist) (n=51) plus 150 IU of HMG/day after 11 days of GnRH-a treatment AC, artificial cycle; GnRH-a, gonadotrophin-releasing hormone agonist; HADS, Hospital Anxiety and Depression Scale; HMG, human menopausal gonadotrophin; i.n., intranasal; c-IVF, conventional in vitro fertilization; n-IVF, non-conventional in vitro fertilization; IQR, interquartile range; NC, natural cycle; LHRH, luteinizing hormone-releasing hormone; r-FSH, recombinant follicle-stimulating hormone; s.c., subcutaneous; SD, standard deviation. Frontiers in Psychiatry | www.frontiersin.org 5 May 2020 | Volume 11 | Article 479 González-Rodrı´guez et al. Psychopathology and Infertility Treatment TABLE 2 | Methods and results of published clinical trials reporting psychopathological complications with hormonal treatments for infertility (n=8). Author and year of Trial objectives Psychopathological assess- Outcomes Main results publication ment (scales, interviews) Haemmerli Keller To compare the psychological burden CES-D Mean (pre-post) NC‐IVF patients had significantly lower et al. (32) of conventional IVF with gonadotropin Brief Symptom Inventory differences in level of depression than cIVF patients. stimulation and IVF without CES-D between both gonadotropin stimulation arms† Greco et al. (33) To evaluate clinical pregnancy rates of HADS Mean (pre-post) No significant differences were found two methods of endometrial differences in between both groups in anxiety and preparation for frozen-thawed single HADS scores between depression scores before starting euploid blastocyst transfer: modified both arms† treatment, on the days of progesterone natural and artificial cycle with GnRH administration, at the blastocyst transfer, agonist suppression and at the pregnancy test To compare psychological distress between both strategies Mamata et al. (34) To understand physical and HADS Mean (pre-post) No statistically significant differences were psychological burden in women under HSCL Somatization subscale differences in found in physical or psychological burden fertility treatment HADS scores between between the protocols (GnRH antagonist To compared GnRH antagonist both arms† and GnRH agonist) protocol with GnRH agonist in terms of physical and psychological burden Stenbæk et al. (3) To investigate whether women Profile of Mood States Mean (pre-post) Although the GnRH antagonist protocol exposed to GnRH agonist protocols Perceived Stress Scale differences in was associated with mood fluctuations exhibit higher levels of mental distress Major Depression Inventory MDI scores between during the stimulation phase, mood compared to women under GnRH both arms† disturbances were not induced by either antagonist protocols of the protocols Bloch et al. (2) To determine whether affective Brief Symptom Inventory Mean (pre-post) GnRH agonist-induced hypogonadal symptoms appear with the use of State-Trait Anxiety Inventory differences in CES-D states were not associated with increased GnRH agonists inducing hypogonadic CES-D scores between long- mood symptoms. Both protocols (short states during IVF cycles and short-protocols† and long) were comparable in their effects To compare long- (inducing on the induction of affective symptoms hypogonadism) and short-protocols (without hypogonadism) de Klerk et al. (36) To compare the impact of HADS Mean (SD) on HADS At the first IVF treatment cycle, mild unsuccessful IVF on women’s (depression scores) ovarian stimulation (including GnRH psychological symptoms between mild after treatment antagonists) was associated with fewer and standard protocols % of significant short-term depressive symptoms than To compare self-reported symptoms depression conventional protocols of depression between both protocols Heijnen et al. (35) To investigate whether mild and Assessment (baseline, 1 week Differences in HADS No statistically significant differences in standard protocols differ in the after outcomes): scores after each IVF depressive or anxious symptoms between proportion of term livebirths and HADS cycle (represented in the protocols women’s well- being, and cost per HSCL Somatization subscale Figure) between both couple Subjective Sleep Quality Scale arms Tapanainen et al. (37) To investigate successful outcomes of Ad hoc questionnaire with a Mean (SD) scores after Buserelin group: higher incidence of IVF treatment with goserelin depot subjective estimation scale of treatment† tiredness, depression, headache and versus buserelin acetate different side effects (e.g., abdominal pain than the goserelin group. tiredness, depression and No differences between the groups in irritability) (scores from 1 = mental irritability, nausea, or swelling. absent to 5 = severe) † Effect sizes for the change (pre-post) in depressive symptoms for each treatment arm could be calculated (see Table 3). CES-D, Center for Epidemiologic Studies Depression Scale; HSCL, Hopkins Symptom Checklist; HADS, Hospital Anxiety and Depression Scale; HMG, human menopausal gonadotrophin (HMG); IVF, in vitro fertilization; NC-IVF, non-conventional in vitro fertilization; SD, standard deviation. (buserelin acetate) combined with oestradiol valerate (33). The (Table 3), both treatment arms were associated with worsening authors did not find statistically significant differences between of depressive symptoms, although a greater negative effect was both groups in terms of anxiety and depressive symptoms, seen in the protocol using GnRH agonists (g = -1.22) when neither before the beginning of treatment, nor on the following compared to the natural cycle protocol (g = -0.53), that did not days after progesterone administration, blastocyst transfer or at include gonadotropin stimulation. It is important to underscore the pregnancy test (33), suggesting that the use of GnRH agonists that mean (SD) HADS scores for both groups were below 7, show similar psychological effects compared to blastocyst which suggests that depressive symptoms were mild, because a transfer in a modified natural cycle. However, when calculating cut-off score ≥ 8 is thought to be appropriate for detecting major the effect sizes for longitudinal changes in depressive symptoms depression in the general practice (38). Frontiers in Psychiatry | www.frontiersin.org 6 May 2020 | Volume 11 | Article 479 González-Rodrı´guez et al. Psychopathology and Infertility Treatment TABLE 3 | Effect sizes of changes in depressive symptoms in studies exploring the effect of hormonal treatments for infertility. Study Assessment scale Arm N Before After Effect size measures treatment treatment Mean SD Mean SD g d 95% CI limits Haemmerli Keller et al. CES-D NC-IVF Pre (N = 57) 12.7 7.3 13.4 10.9 -0.07 -0.38 to 0.23 (32) (no gonadotropin stimulation or very low Post (N = 44) doses of clomiphene) CES-D cIVF Pre (N = 62) 12.2 8.6 15.7 7.9 -0.42 -0.73 to -0.12 (HMG + GnRH antagonist) Post (N = 45) Greco et al. (33) HADS-D Modified-NC 109 5.3 1.8 6.1 1.1 -0.53 -0.75 to -0.32 (no gonadotropin stimulation; oocyte maturation with hCG) HADS-D Artificial cycle 113 4.9 1.5 6.8 1.6 -1.22 -1.47 to -0.98 (GnRH agonist) Mamata et al. (34)§ HADS-D GnRH antagonist 232 -0.1 3.6 -0.03 NA# HADS-D GnRH agonist 460 0.1 3.7 0.03 NA# Stenbæk et al. (3)† MDI GnRH antagonist 42 8.7 9.6 8.2 7.3 0.06 -0.25 to 0.37 MDI GnRH agonist 41 6.3 3.8 7 5.4 -0.15 -0.47 to 0.17 Bloch et al. (2) CES-D Long-protocol 48 32.5 7.6 36.2 9.4 -0.43 -0.073 to -0.13 (GnRH agonist for 14 days+ r-FSH) CES-D Short- protocol 60 30.6 8.5 34.3 9.7 -0.40 -0.67 to -0.14 (GnRH agonist + r-FSH from first day of the cycle) Tapanainen et al. (37)‡ Subjective depressive Goserelin 49 1.11 0.50 1.27 0.55 -0.30 -0.59 to -0.02 symptoms (GnRH agonist) Subjective depressive Buserelin 51 1.35 0.87 1.59 1.04 -0.25 -0.53 to 0.03 symptoms (GnRH agonist) g, Hedges’ g; d, Cohen’s d; SD, standard deviation; CI, confidence intervals; CES-D, Center for Epidemiologic Studies Depression Scale; cIVF, in vitro fertilization with gonadotropin stimulation; AC, artificial cycle; NC, natural cycle; NC-IVF, in vitro fertilization without gonadotropic stimulation; GnRH, gonadotropin- releasing hormone; HMG, human menopausal gonadotropin; r-FSH, recombinant follicle-stimulating hormone; HADS-D, Hospital Anxiety and Depression Scale—depression subscore; MDI, Major Depression Inventory; NA, not assessed. § In the Mamata et al. (34) study, mean differences in HADS-D were reported. Hedges g’ was calculated taking into account this information. † As median and interquartile range were reported in the study by Stenbæk et al. (3), mean (SD) was computed as suggested by Wan et al. ‡ In the Tapanainen et al. (37) study, mean (SD) changes in subjective symptoms of depression were obtained from figures with t he procedure described by Labad et al. (28). # d Cohen confidence interval limits were not calculated because means and standard deviations for baseline and final visits were not available. Stenbaek et al. (3) carried out a randomized trial in a total of depressive symptoms was higher in those receiving GnRH 83 women undergoing treatment for infertility (3). Patients were agonists compared to those under GnRH antagonists, randomized to the GnRH antagonist protocol, which included suggesting that women undergoing IVF/ICSI may suffer from daily injections with r-FSH treatment, and GnRH agonists, higher depressive symptoms than women not undergoing these which were administered intranasally. Mood symptoms and treatments, irrespective of the protocol assigned. neuroticism traits were evaluated by self-reported assessment With the main hypothesis that GnRH agonists may be scales. The authors found that neuroticism was associated with responsible for the induction of depressive symptoms in higher scores on psychological distress, independent of the women undergoing IVF, Bloch and co-workers (2) carried out protocol received. Mental distress associated with ART a prospective randomized trial with two main treatment groups: treatments may not be attributed to hypogonadism or any a short protocol and a long protocol (2). The long protocol protocol (3). In terms of depressive symptoms, although consisted of the subcutaneous administration of the GnRH GnRH agonists seemed to show a slightly poorer profile than agonist triptorelin for 14 days. 225 IU of recombinant FSH (r- GnRH antagonists, effect sizes were very small (Table 3), without FSH) were administered in a second step. The short protocol was significant pre-post changes. defined by the administration of the GnRH agonist from the first Similarly, Mamata et al. (34) carried out a trial across 12 IVF day of the cycle, followed by concomitant 225 IU r-FSH. The centres in India (34). The authors divided participants into two authors hypothesized that a long protocol may induce prolonged groups according to the type of treatment they received: a) hypogonadism compared to a short protocol, a fact that may GnRH antagonists and b) GnRH agonists. Psychopathological increase levels of psychological distress and may be associated symptoms and somatic distress symptoms were assessed by with higher depressive symptoms (2). The authors found a means of the Hospital Anxiety and Depression Scale (HADS) significant increase in depressive and anxiety symptoms during and the Hopkins Symptom Check List (HSCL) during two IVF-ET cycles, which were higher between the hypogonadal treatment visits. Although no statistically significant differences phase and the peak in gonadotropin stimulation, at later points in depressive or anxiety symptoms were found between both in treatment. The hypogonadal state which was GnRH agonist- protocol groups, the percentage of individuals who reported induced was not found to be associated with increased mood Frontiers in Psychiatry | www.frontiersin.org 7 May 2020 | Volume 11 | Article 479 González-Rodrı´guez et al. Psychopathology and Infertility Treatment symptoms, suggesting that neither long nor short protocols were with regular menstrual cycles who suffered from unexplained correlated with an increase in depression. Effect sizes for the infertility (39). The main goal of this trial was to explore change in depressive symptoms suggest that both protocols are psychopathological symptoms and physical concerns in women associated mild mood worsening (Table 3). receiving clomiphene citrate for superovulation with intrauterine De Klerk et al. (36) investigated the psychopathological effect insemination. Women were randomized to treatment with of IVF treatment on women undergoing mild ovarian clomiphene citrate or placebo and received this intervention on stimulation (including GnRH antagonist and single embryo days 3–7 of their menstrual cycle. Ten patients received transfer) compared to an standard strategy (long-protocol with clomiphene citrate 50 mg daily and then placebo daily, and 10 GnRH agonist and double embryo transfer) (36). After IVF women received placebo and then clomiphene citrate daily. treatment, women with negative outcome were more likely to Physical, behavioral, and mental symptoms were explored by present depressive symptoms 1 week after the end of treatment using the following assessment scales: Follicular Cycle Total compared to women who received mild IVF treatment. The Physical Score for the Calendar of Premenstrual Experiences prevalence of possible depressive disorder (defined as a HADS (COPE) self-assessment, the Follicular Cycle Total Behavioral score>7) was 38.8% for the women in the standard IVF group Score for the Calendar of Premenstrual Experiences (COPE) self- who underwent multiple IVF cycles against 19.4% of the women assessment, the Luteal Cycle Total Behavioral Score for the in the mild IVF group (p = 0.04). The authors associated these Calendar of Premenstrual Experiences (COPE) self-assessment results with the prolonged ovarian suppression by GnRH and the Luteal Cycle Total Physical Score for the Calendar of agonists in those women who underwent the standard IVF, Premenstrual Experiences (COPE) self-assessment. Although suggesting that these treatments may lead to more symptoms not statistically relevant, patients receiving placebo showed of depression. higher scores than those receiving clomiphene citrate on the Heijnen et al. (35) carried out a randomized, open-label, non- Follicular Cycle Behavioral and Physical Scores (COPE). No inferiority trial in 404 women with an indication for IVF or ICSI other differences in median scores were found in behavioral, in the Netherlands, of whom 205 received mild ovarian mental, and physical symptoms as measured by the luteal scales. stimulation (single embryo transfer with the administration of GnRH antagonists) and 199 were given standard ovarian stimulation with the transfer of two embryos and with the Quality Assessment and Risk of Bias The assessment of the risk of bias has been presented in detail in administration of GnRH agonists (35). The authors assessed Table S2. Of all nine clinical trials included in our systematic depressive symptoms and anxiety by means of the HADS and review, four were considered to be good (2, 3, 36, 39), four fair found no statistically significant differences in psychopathological (33–35, 37), and only one (32) had poor quality. symptoms between both groups (35). We did not identify any trial publication or non-publication One of the most relevant studies was the randomized trial of results regarding the occurrence of psychotic symptoms in carried out by Tapanainen et al. (37). In this IVF study, patients women undergoing fertility treatments. received two types of GnRH agonists. Individuals were randomized to treatment with long-acting subcutaneous goserelin or with intranasally administered buserelin acetate. They both stimulate the production of testosterone and DISCUSSION oestrogen in a non-pulsatile manner, which results in the downregulation of both sex hormone systems (37). After 11 In this paper, we carried out a systematic review on available days of the administration of either goserelin or buserelin, the work on the psychopathological effects of hormonal treatments administration of 150 IU of HMG/day was started. The authors for infertility on women and the effects of these therapies on the found that patients receiving buserelin reported more depressive occurrence of newly diagnosed mood and psychotic disorders. mood, tiredness, and headache 1 week after starting the GnRH Finally, nine trials were included, all of them in non-clinical agonist, when compared to those treated with goserelin (37). populations. Four trials compared GnRH agonists and GnRH However, when considering the effect sizes for the change in antagonists (3, 34–36), showing a better mood profile (less depressive symptoms during the study, both protocols had depressive symptoms) for those hormonal protocols including similar effects (mild worsening) on mood (Table 3). antagonists in one trial. Two trials compared protocols using either GnRH agonists or GnRH antagonists versus natural cycle Non-Published Studies Designed to protocols that did not use gonadotropin stimulation, reporting a Assess Psychopathology in Women better mood profile in those protocols without gonadotropin Receiving Hormonal Treatments for stimulation (32, 33). Other two studies comparing long and short Infertility (Completed or Ongoing) protocols of GnRH agonists (2) and two GnRH agonists One trial was registered at clinicaltrials.gov and reported to (buserelin and goserelin) (37) did not find significant be completed. differences in mood changes between treatment arms. An In 2010, Pittman et al. started a double-blind, placebo- unpublished study compared two patterns of clomiphene vs controlled, crossover clinical trial in 20 menstruating women placebo administration with no differences between groups (39). Frontiers in Psychiatry | www.frontiersin.org 8 May 2020 | Volume 11 | Article 479 González-Rodrı´guez et al. Psychopathology and Infertility Treatment Most previous published trials evaluated the effect of either associated with GnRH agonist ovarian suppression in GnRH antagonists or GnRH agonists on the occurrence of newly menopause could reflect mainly the effects of ovarian diagnosed depressive disorder or depressive symptoms for the first suppression on women who are more vulnerable to the time in women. None of them investigated the risk or prevalence of development of depression or who are currently depressed relapses in women with a previous diagnosis of depressive disorders (47). However, once again, no clinical trials have explored the or psychotic disorders. When focusing on hormonal compounds effect of leuprolide on women undergoing fertility treatments. other than GnRH agonists or antagonists, one recent trial has been Bloch and collaborators (2) investigated the relationship developed to study the effect of clomiphene citrate on women under between affective symptoms and gonadal steroids during in the IVF protocol (39). Moreover, in the study by Haemmerli Keller vitro fertilization (2). They found that the drop from high et al. (32), patients under the protocol without gonadotropin oestradiol levels at the oestradiol phase to lower levels at the stimulation could receive low doses of clomiphene (32). This progesterone phase was correlated with increasing depressive latter study suggests that the lack of gonadotropin stimulation is symptoms, suggesting that the abrupt decline in oestrogen levels associated with fewer changes in mood, as the effect size was very can precipitate negative mood states. This fact may be small (g = -0.07). responsible for the variability of the presence of depressive Celano et al. (40) and Wilkins and collaborators (41) pointed symptoms in women undergoing IVF (2). This may be out that GnRH agonists (e.g., leuprolide and goserelin) induce partially in line with some observational studies exploring the hypogonadism (40, 41), which could be related to different prevalence of depressive symptoms in women undergoing psychiatric side effects. In the information about these fertility treatments. Particularly, Volgsten and co-workers (22) hormonal drugs (42, 43), depressive symptoms also seem to be carried out an observational study including couples undergoing reported. These findings have been replicated in subsequent case IVF or ICSI and applied the Primary Care Evaluation of Mental series (44, 45) and retrospective studies, including the report of a Disorders (PRIME-MD) system, which is a tool to evaluate the patient treated with leuprolide (46). Furthermore, prophylactic prevalence of psychiatric disorders according to 2% in men, treatment with SSRIs has been reported to prevent the being major depression the most commonly found, irrespective development of depressive symptoms in these patients (45). of the hormonal compound they received. More recently, other In our systematic review, we found that patients receiving studies have reported that pregnant women after fertility ovarian stimulation with GnRH antagonists had increased treatment did not differ in terms of depressive symptoms depressive symptoms compared to patients who did not compared to those naturally pregnant, suggesting that the receive ovarian stimulation (32). One study suggested that treatment did not have a negative impact on mood (23). treatment with one GnRH agonist, buserelin, had a poorer However, the hormonal compounds were not included in the mood profile than other GnRH agonist (goserelin) 1 week later discussion. Evans-Hoeker et al. (48) carried out a cohort study but showed similar mood changes at the end of the trial (37). including participants in two previous randomized trials, namely However, GnRH agonists did not seem to differ from GnRH PPCOS II and AMIGOS (48). The first trial compared patients antagonists in their associated occurrence of depressive treated with clomiphene citrate versus letrozole, and the second symptoms, s ugge st ing that n either protocol has a compared gonadotropins, clomiphene citrate and letrozole. Both psychopathological effect on women undergoing fertility studies assessed whether maternal depression would have an treatments (3, 34–36). influence on pregnancy outcomes after non-IVF fertility In contrast, Ben Dor et al. (47) studied the effect of GnRH therapies. They did not find any negative effect of current agonists on a sample of 72 healthy women (medication-free; not active depression on non-IVF outcomes. The effect of pregnant; no significant past or current medical illness; reported hormonal compounds used in fertility treatment on the regular menstrual cycles; and normal physical, gynaecological recurrence of major depression have been poorly investigated. examinations, and laboratory results) (47). The absence of Sejbaek et al. (49) carried out a register-based national cohort current or past Axis I psychiatric illness was confirmed by study including women undergoing IVF, ICSI, and other embryo Structured Clinical Interview for DSM-IV. The objective of the transfer treatments (49). Women with a previous diagnosis of study was to better understand whether the acute induction of depression had lower rates of live births. The authors did not find hypogonadism may determine significant depressive symptoms statistically significant differences in rates of depression, but they in healthy premenopausal women, which individual symptoms recommended that women with previous depression may may be associated with hypogonadism and increase susceptibility require specific psychiatric attention before starting a new to depression and whether changes in plasma levels of ovarian treatment. In the same line, other authors highlight that a hormones correlate with changes in mood symptoms (47). After history of major depression would be a significant predictor a 2-month screening phase, every woman received the first dose for major depression during fertility treatment (50). Psychosocial of depot leuprolide acetate. Relative to baseline, induced support and interventions addressed to women with a previous hypogonadism with GnRH agonist was associated with history of depression have been recommended when initiating significantly decreased sexual interest, disturbed sleep, and hot infertility treatment. flashes but no significant change in any mood-related symptom We did not find any clinical trial specifically investigating the scores (47). The authors proposed that depressive symptoms effects of hormonal treatments on depressive symptoms in Frontiers in Psychiatry | www.frontiersin.org 9 May 2020 | Volume 11 | Article 479 González-Rodrı´guez et al. Psychopathology and Infertility Treatment unipolar or bipolar disorder patients. In a recent prospective in women with and without psychotic disorders prior to the observational study that included women receiving infertility treatment (25), as a part of a cohort of 42,915 Danish women treatments with a history of major depressive disorder or bipolar undergoing fertility treatments. Women with previous diagnosis of disorder (24), a high risk of depressive relapse was found, even in psychotic disorder had lower rates of success compared to non- those women maintaining psychotropic medication. These psychotic women. The authors did not evaluate depressive results suggest that maintenance of medication is not sufficient symptoms as the main outcomes. to avoid affective relapses. In our systematic review, we did not Several limitations in this systematic review should be find clinical trials assessing recurrences in patients with considered. The most important limitation of this systematic affective disorders. review is the absence of a sufficient number of published articles Women with polycystic ovary syndrome (PCOS) show an on the psychopathological effects of hormone compounds used increased prevalence of higher depression and anxiety scores and in infertility treatments in women. Furthermore, most clinical increased odds of moderate and severe depressive and anxiety trials included in our systematic review excluded patients with a symptoms compared with controls (51). On the other hand, a psychiatric history or psychopathological treatment. Therefore, few studies that have evaluated the impact of PCOS-related these exclusion criteria might bias the evidence because most treatments (lifestyle interventions and pharmacotherapy) on studies excluded women with mental illnesses. Although the mood have reported no detrimental effect or even some quality of selected clinical trials was fair to good in most cases (8/ improvement in depressive and anxiety symptoms and quality 9 = 89%), as none of them included patients with serious mental of life (51). In addition, clomiphene citrate, a selective oestrogen illnesses, the research field needs to conduct more inclusive receptor modulator used to induce ovulation, even in patients clinical trials to overcome this limitation. with PCOS, has been associated with mood lability and The prediction of acute exacerbations or the occurrence of depressed mood in two cross-sectional studies (52, 53). In the newly diagnosed mental disorders is limited by the scarce cross-sectional, self-report survey of Choi et al. (53), 41% of literature in the field. Furthermore, most studies were focused clomiphene-treated women experienced depressed mood, and 75 on depressive or anxiety symptoms, and they did not assess, in of 162 (45%) experienced mood swings during treatment (53). general, psychopathological symptoms according to the most Mood changes (54), suicidal behavior (55), and visual commonly used assessment scales for depression. Several hallucinations (56) have also been associated with clomiphene authors have reported that psychotic symptoms may occur treatment in case reports. during fertility treatments, during or after the use of hormone None of the selected published clinical trials in our systematic compounds; however, to date, few studies have focused on patients review specifically investigated the psychopathological effects of suffering from schizophrenia and other psychotic disorders. Most the use of clomiphene citrate in the treatment of infertility on of them are case reports or case series, and trials are still lacking on women. In an unpublished randomized double-blind crossover this topic. To the best of our knowledge, this is the first systematic trial in 20 women (53), clomiphene treatment was not associated review on the psychopathological effects of hormonal treatments with mood or behavioral changes, a result that contrasts those of for infertility. Although the number of selected clinical trials was other studies suggesting that clomiphene induces psychological low, our systematic review opens new avenues on the investigation side effects quite frequently (53). of hormone effects in women undergoing infertility treatments. In relation to patients with psychotic disorders, to the best of our Future studies need to include patients with major mood and knowledge, no clinical trials have evaluated the psychopathological psychotic disorders. effects of hormonal treatments for infertility on women diagnosed with bipolar disorder, schizophrenia, or other psychotic disorders. A case report linked the use of leuprolide acetate for in vitro fertilization (IVF) treatment to a psychotic exacerbation in a 37- AUTHOR CONTRIBUTIONS year-old woman who suffered from a previous schizoaffective psychosis (57). In this line, a case series of Purvin (58) showed AG-R and JC conducted the screening and selection processes. different visual disturbances (some of them persistent) secondary to AG-R, JC, VS, CG-R, MB, JM and JL contributed to the clomiphene citrate treatment in three women treated for infertility conceptualization and writing of this manuscript. All authors with clomiphene for 4 to 15 months (58). In a review by Seeman have approved the final version of the manuscript. (59), there were five case reports of a self-limited psychotic disorder induced by clomiphene (59). All cases were reported to start psychotic symptoms during treatment, to have a paranoid FUNDING component and to stop when the drug was withdrawn. We did not find any trial reporting the potential effects of hormones used in This study was supported in part by a grant from the Catalan fertility treatments on women with psychosis or the occurrence of Agency for the Management of University and Research Grants psychotic symptoms in non-diagnosed women. However, some (AGAUR 2017 SGR 632). The funder had no role in the study case reports have been reported on the use of clomiphene. A recent design, data collection and analysis, decision to publish, or national register study compared success rates of fertility treatments preparation of the manuscript. Frontiers in Psychiatry | www.frontiersin.org 10 May 2020 | Volume 11 | Article 479 González-Rodrı´guez et al. Psychopathology and Infertility Treatment ACKNOWLEDGMENTS SUPPLEMENTARY MATERIAL JL received an Intensification of the Research Activity Grant The Supplementary Material for this article can be found online (SLT006/17/00012) from the Health Department of the at: https://www.frontiersin.org/articles/10.3389/fpsyt.2020. Generalitat de Catalunya. 00479/full#supplementary-material REFERENCES 18. Holka-Pokorska J, Jarema M, Wichniak A. Clinical determinants of mental disorders occurring during the infertility treatment. Psychiatr Pol (2015) 1. Rooney KL, Domar AD. The relationship between stress and infertility. 49:965–82. doi: 10.12740/PP/35958 Dialogues Clin Neurosci (2018) 20:41–7. 19. Soares CN, Zitek B. Reproductive hormone sensitivity and risk for depression 2. Bloch M, Azem F, Aharonov I, Ben Avi I, Yagil Y, Schreiber S, et al. 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The use, distribution or appi.ajp.2012.12010117 reproduction in other forums is permitted, provided the original author(s) and the 48. Evans-Hoeker EA, Eisenberg E, Diamond MP, Legro RS, Alvero R, Coutifaris copyright owner(s) are credited and that the original publication in this journal is C, et al. Major depression, antidepressant use, and male and female fertility. cited, in accordance with accepted academic practice. No use, distribution or Fertil Steril (2018) 109:879–87. doi: 10.1016/j.fertnstert.2018.01.029 reproduction is permitted which does not comply with these terms. Frontiers in Psychiatry | www.frontiersin.org 12 May 2020 | Volume 11 | Article 479