Fertility and Sterility
Volume 95, Issue 1 , Pages 307-309, January 2011

GnRH-agonist induced depressive and anxiety symptoms during in vitro fertilization–embryo transfer cycles

Presented in part at the 13th Israel Society of Biological Psychiatry, Hagoshrim, Israel, March 3-5, 2009.

  • Miki Bloch, M.D.

      Affiliations

    • Department of Psychiatry, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
    • Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    • Corresponding Author InformationReprint requests: Miki Bloch, M.D., Psychiatric Department, Tel Aviv Sourasky Medical Center, 6 Weizman St., Tel Aviv, Israel 64239 (FAX: 97236975774).
    • ,
  • Foad Azem, M.D.

      Affiliations

    • Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    • IVF Unit, Lis Women’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
    • ,
  • Inbar Aharonov, M.Sc.

      Affiliations

    • Department of Psychiatry, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
    • ,
  • Irit Ben Avi, Ph.D.

      Affiliations

    • Department of Psychiatry, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
    • ,
  • Yaron Yagil, Ph.D.

      Affiliations

    • Department of Psychiatry, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
    • ,
  • Shaul Schreiber, M.D.

      Affiliations

    • Department of Psychiatry, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
    • Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    • ,
  • Ami Amit, M.D.

      Affiliations

    • Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    • IVF Unit, Lis Women’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
    • ,
  • Abraham Weizman, M.D.

      Affiliations

    • Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    • Geha Mental Health Center and the Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Petah Tikva, Israel

Received 16 June 2010; received in revised form 16 July 2010; accepted 16 July 2010. published online 31 August 2010.

Article Outline

To determine whether the use of a GnRH agonist inducing a hypogonadic state during IVF-ET cycles induces negative mood symptoms, we conducted a prospective randomized study in 108 women comparing two different controlled ovarian stimulation protocols. A significant phase effect was observed for depression and anxiety symptoms during IVF-ET cycles reflecting an increase in symptoms between the hypogonadal phase and the peak in gonadotropin stimulation; however, the hypogonadal phase induced by the GnRH agonist was not associated with a significant increase in any of the studied mood parameters.

Key Words: In vitro fertilization, GnRH agonist, estradiol, progesterone, depression, anxiety, mood

 

In vitro fertilization–embryo transfer (IVF-ET) is associated with psychological strain, decreased emotional well-being, elevated anxiety, and even severe depression 1, 2. Psychological stress is the most common reason for discontinuation of the IVF-ET (3).

Ovarian stimulation protocols are based on the administration of gonadotropins and GnRH agonists (GnRH-a) for inducing down-regulation of GnRH receptors and consequent hypogonadism (4). Use of GnRH-a can induce negative mood symptoms such as depressed mood, anhedonia, fatigue, and anxiety, which are attributed to induced hypogonadism 5, 6, 7, 8, 9. Symptomatic relief was achieved by cotreatment with sertraline or E2 valerate 10, 11. Gonadotropin-releasing hormone–agonist–induced hypoestrogenism during IVF-ET cycles has been reported to be associated with significant mood symptoms (12).

We assessed affective symptoms as a function of induced ovarian steroid states during IVF-ET. Our hypothesis was that a “long protocol,” inducing hypogonadism, will be associated with increased levels of psychological distress when compared with phases of elevated E2 or P, or when compared with a “short protocol” in which a hypogonadal state is not induced.

The local Institutional Review Board committee approved the study (ID#04-284, registered on ClinicalTrials.gov IDNCT01032421). All women admitted between 2006 and 2007 were screened for eligibility and gave their written informed consent. Of 250 women assessed, 121 met the inclusion-exclusion criteria of first or second IVF-ET cycle, age <42 years, no endometriosis, no history of testicular sperm extraction, and no concurrent psychotherapeutic or psychopharmacologic treatment. Participation of 13 women was terminated because of lack of response or cooperation. The mean age was 31.8 ± 5.4 years, mean duration of infertility was 2.6 ± 2.5 years, and for 75% it was their first IVF-ET cycle.

Participants were assigned randomly to either short (n = 60) or long (n = 48) protocols and were comparable in demographic and clinical parameters. The long protocol began with the administration of SC injections of 0.1 mg/d of the GnRH-a triptorelin (Decapeptyl; Ferring, Kiel, Germany) for at least 14 days, followed by concomitant 225 IU of recombinant-FSH (r-FSH), (Gonal-F; Serono, Geneva, Switzerland). For the short protocol, administration of GnRH-a began from the first day of the cycle followed by concomitant daily 225 IU r-FSH and GnRH-a. Choriogonadotropin alfa 250 mcg (Ovitrelle; Serono, Geneva, Switzerland) was administered when at least three follicles achieved 18-mm diameter. Ovum pickup was performed 36 hours later. Fertilization was performed by conventional IVF, and ET was performed 48 to 72 hours later. Micronized progesterone (200 mg three times per day, Utrogestan; Besins International Laboratories, Paris, France) was given for luteal support. Pregnancy was determined 12 days later.

Assessment was performed at four points: [1] during menses (T0, baseline); [2] 2 weeks after the first GnRH-a injection (T1, hypogonadal phase of the long protocol); [3] approximately 10 days after initiation of gonadotropins and before ovum pickup (T2, follicular phase); and [4] 12 days after ET, before the β-hCG (T3, luteal phase). The timing of T3 was selected to be physically unstressful and far enough into the procedure so that the psychological effect would be perceivable.

State psychological measures were assessed by the Derogatis Brief Symptoms Inventory (13), Spielberger’s State Anxiety Inventory for anxiety 14, 15, and the Center for Epidemiologic Studies depression scale for depression 16, 17. Plasma was stored at −80°C until assayed. Serum measurements of E2 and P were performed with commercial kits (Electrochemiluminescence Immuno Assay Elecsys 2010; Roche, Basel, Switzerland). Within- and between-run coefficient of variation values were 1.4% and 2.1%, respectively.

Means, SDs, and ranges were used as descriptive statistics. Comparisons between groups were made with use of χ2 tests with respect to nominally scaled variables and use of repeated-measures ANOVA for continuous variables. Post hoc analysis was performed by Tukey’s test. Pearson’s correlation coefficients and Spearman’s rank correlation coefficients were calculated for continuous variables and ordinal variables, respectively. All tests were two-sided, and the required significance level was .05.

No difference in gonadal steroids (GS) levels were observed between the groups at T0, T2, or T3. Progesterone levels were significantly higher in women who subsequently were pregnant (72.9 ± 54.3 ng/mL) than in nonpregnant women (10.5 ± 14.9 ng/mL; P<.000001). Both protocols showed a significant phase effect for depression and anxiety, reflecting symptom elevation mostly from T1 to T2 (Table 1). Other modules of the Brief Symptoms Inventory questionnaire that increased significantly were somatization for both short and long protocols (F[2, 108] = 10.0, P=.0001, and F[3, 132] = 3.7, P=.014, respectively) and obsessive compulsive (F[3, 132] = 3.4, P=.019) for the long protocol only. Along the time points no significant interaction was found between the study groups for either depression or anxiety.

Table 1. Depression and anxiety scores for the two study groups during the different phases of the IVF-ET cycle.
Psychometric testProtocol (group)Baseline T0Hypogonadal T1Follicular T2Luteal T3FP valuea
CESDLong32.46 ± 7.5732.34 ± 8.5834.56 ± 9.0636.23 ± 9.443.8.01
Short30.61 ± 8.46—34.32 ± 9.7434.36 ± 11.876.7.002
Long × short 0.9.41
STAILong40.54 ± 8.5139.68 ± 8.9542.37 ± 10.6345.7 ± 10.886.9.00
Short38.15 ± 9.94—43.71 ± 12.2744.10 ± 12.8711.7.00
Long × short 2.3.1
BSI-depressionLong0.53 ± 0.450.55 ± 0.540.60 ± 0.600.61 ± 0.660.4.76
Short0.41 ± 0.54—0.57 ± 0.630.56 ± 0.613.4.04
Long × short 0.3.76
BSI-anxietyLong0.71 ± 0.590.72 ± 0.780.76 ± 0.690.83 ± 0.760.7.55
Short0.63 ± 0.59—0.80 ± 0.660.85 ± 0.774.4.01
Long × short 0.2.80
BSI-GSILong0.51 ± 0.430.57 ± 0.530.62 ± 0.580.59 ± 0.551.5.21
Short0.43 ± 0.41—0.55 ± 0.480.57 ± 0.583.8.03
Long × short 0.01.99

Note: Values are expressed as mean ± SD. BSI = Derogatis brief symptoms inventory; BSI-GSI = Derogatis brief symptoms inventory–global severity index; CESD = center for epidemiologic studies depression scale; STAI = spielberger’s state anxiety inventory.

aANOVA–repeated measures.

An analysis of the long protocol revealed no association of the hypogonadal phase with the emotional parameters. Post hoc analysis showed no change in depression or anxiety between T0 and T1. However, a significant elevation in symptoms was found from both baseline T0 and hypogonadal phase T1 to the luteal phase T3 for depression (P=.033 and .022, respectively) and anxiety (P=.002 and .0001, respectively). The increase in mood scores between T2 and T3 was not significant for either depressive (P=.35) or anxiety (P=.12) symptoms.

The main finding of this study is that the GnRH-a–induced hypogonadal state is not associated with increased mood symptoms. Such an increase was observed at later points in the treatment cycle, specifically after gonadotropin treatment when E2 levels are elevated and 2 weeks after ET when P levels are high. However, the two protocols were comparable in the induction of mood symptoms.

Our results do not replicate the previous preliminary report of Toren et al. (12) of an increase in depression and anxiety scores during the hypogonadal phase in women receiving treatment with a GnRH-a during IVF-ET. The present study’s larger sample of well-characterized women most probably better reflects the relationship beween GNRH-a administration and the emergence of mood symptoms.

Because hypogonadal E2 levels previously have been implied in the exacerbation of mood symptoms 5, 6, 7, 9, 11, the lack of negative mood induction in this study is somewhat surprising. Furthermore, lower E2 levels were reported during the follicular phase in women with depression, a finding that was used to argue for the importance of normal levels of E2 for the prevention of mood disorders (18). This argument has considerable biologic support because E2 significantly affects multiple brain systems including memory, synaptic density, and serotonin and norepinephrine neurotransmission 19, 20, 21.

However, the clinical and natural history of several reproductive-related mood disorders does not support this hypothesis. The prevalence of depression is high in women in reproductive age when estrogen levels are high. Moreover, the incidence of depression peaks during the perimenopause when GS levels fluctuate, rather than during menopause, a state of GS deficiency with relatively low incidence of depression 22, 23, 24, 25. Furthermore, premenstrual dysphoric disorder and postpartum depression, both GS-related mood syndromes, are associated with a fluctuating rather than stable hypogonadal state. In fact, it has been reported that induction of hypogonadism for 2 to 3 months in premenopausal women does not significantly induce negative mood symptoms (26). Thus, it may be argued that it is not low levels of E2 per se that underlie the emergence of depression in women, but rather their cyclicity (27).

A possible explanation for the lack of effect of GnRH-a on mood symptoms in this paradigm is that it is not the absolute hypogonadic state that induces negative mood but the rapidity and magnitude of change in GS levels. Because in this paradigm GnRH-a is administered during menses when GS levels are low, there is no significant further drop in their levels after the GnRH-a administration, and hence no effect on mood. The lack of association between the hypogonadic state and mood symptoms may also be due to the duration of the induced hypogonadotropic state, which may be too short for clinical relevance (28). Furthermore, being a naturalistic study, the subject population consisted of women without any known predisposition to reproductive-related mood syndromes, and possibly a selected “predisposed” population would have had a more robust response.

Beyond this study’s implications for the understanding of the interaction between GS and mood, it also has direct implications for the IVF-ET procedure. In both protocols a significant elevation in mood symptoms was observed toward the second half of the treatment cycle. This elevation may be related to a nonspecific buildup of stress resulting from the emotional complexity of the procedure. Because both short and long protocols are used in IVF units, our findings strongly argue against the possibility that GnRH-a exacerbates or induces negative mood symptoms during IVF-ET cycles. Thus, when both protocols are considered, clinicians can make their decision on the basis of individual-tailored treatment priorities rather than on the risk of the possible emotional outcome.

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Acknowledgments 

The authors thank Mrs. Yael Shmueli and Mrs. Adel Alon from the IVF unit for their help in recruitment and management of the subjects.

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 M.B. has nothing to disclose. F.A. has nothing to disclose. I.A. has nothing to disclose. I.B.A. has nothing to disclose. Y.Y. has nothing to disclose. S.S. has nothing to disclose. A.A. has nothing to disclose. A.W. has nothing to disclose.

 M.B. and F.A. contributed equally to this article.

 Supported by the National Institute for Psychobiology in Israel.

PII: S0015-0282(10)02199-0

doi:10.1016/j.fertnstert.2010.07.1073

Fertility and Sterility
Volume 95, Issue 1 , Pages 307-309, January 2011

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