GnRH-agonist induced depressive and
anxiety symptoms during in vitro
fertilization–embryo transfer cycles
To determinewhether the use of a GnRH agonist inducing a hypogonadic state during IVF-ET cycles induces neg-
ative mood symptoms, we conducted a prospective randomized study in 108 women comparing two different con-
during IVF-ET cycles reflecting an increase in symptoms between the hypogonadal phase and the peak in gonad-
otropin stimulation; however, the hypogonadal phase induced by the GnRH agonist was not associated with
a significant increase in any of the studied mood parameters. (Fertil Steril?2011;95:307–9. ?2011 by American
Society for Reproductive Medicine.)
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).
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 at-
tributed to induced hypogonadism (5–9). Symptomatic relief was
achieved by cotreatment with sertraline or E2valerate (10, 11).
Gonadotropin-releasing hormone–agonist–induced hypoestrogen-
ism during IVF-ET cycles has been reported to be associated with
significant mood symptoms (12).
We assessed affective symptoms as a function of induced ovar-
ian 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 E2or P, or when compared with a ‘‘short proto-
col’’ in which a hypogonadal state is not induced.
(ID#04-284, registered on ClinicalTrials.gov IDNCT01032421). All
met the inclusion-exclusion criteria of first or second IVF-ET cycle,
tion, and no concurrent psychotherapeutic or psychopharmacologic
treatment. Participation of 13 women was terminated because of
lack of response or cooperation. The mean agewas 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 ¼ 60) or
long (n ¼ 48) protocols and were comparable in demographic and
clinical parameters. The long protocol began with the administra-
tion 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
Miki Bloch, M.D.a,b
Foad Azem, M.D.b,c
Inbar Aharonov, M.Sc.a
Irit Ben Avi, Ph.D.a
Yaron Yagil, Ph.D.a
Shaul Schreiber, M.D.a,b
Ami Amit, M.D.b,c
Abraham Weizman, M.D.b,d
aDepartment of Psychiatry, Tel Aviv Sourasky Medical Center,
Tel Aviv, Israel
bSackler Faculty of Medicine, Tel Aviv University, Tel Aviv,
cIVF Unit, Lis Women’s Hospital, Tel Aviv Sourasky Medical
Center, Tel Aviv, Israel
dGeha Mental Health Center and the Laboratory of Biological
Psychiatry, Felsenstein Medical Research Center, Petah
Received June 16, 2010; revised and accepted July 16, 2010; published
online August 30, 2010.
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.
Presented in part at the 13th Israel Society of Biological Psychiatry,
Hagoshrim, Israel, March 3-5, 2009.
Reprint requests: Miki Bloch, M.D., Psychiatric Department, Tel Aviv
Sourasky Medical Center, 6 Weizman St., Tel Aviv, Israel 64239
(FAX: 97236975774; E-mail: email@example.com).
Fertility and Sterility?Vol. 95, No. 1, January 2011
Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.
oratories, Paris, France) was given for luteal support. Pregnancy
was determined 12 days later.
Assessment was performed at four points:  during menses
(T0, baseline);  2 weeks after the first GnRH-a injection
(T1, hypogonadal phase of the long protocol);  approximately
10 days after initiation of gonadotropins and before ovum pickup
(T2, follicular phase); and  12 days after ET, before the b-hCG
(T3, luteal phase). The timing of T3was 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
tory 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 E2and 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 c2tests
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 be-
tween the groups at T0, T2, or T3. Progesterone levels were signifi-
cantly 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
T1to T2(Table 1). Other modules of the Brief Symptoms Inventory
short and long protocols(F[2, 108]¼ 10.0, P¼.0001,and F[3, 132]
nificant interaction was found between the study groups for either
depression or anxiety.
An analysis of the long protocol revealed no association of the
hypogonadal phase with the emotional parameters. Post hoc anal-
baseline T0and hypogonadal phase T1to the luteal phase T3for
depression (P¼.033 and .022, respectively) and anxiety (P¼.002
and .0001, respectively). The increase in mood scores between
T2and T3was not significant for either depressive (P¼.35) or anx-
iety (P¼.12) symptoms.
The main finding of this study is that the GnRH-a–induced
hypogonadal state is not associated with increased mood symp-
cycle, specifically after gonadotropin treatment when E2levels are
elevated and 2 weeks after ET when P levels are high. However,
the two protocols were comparable in the induction of mood
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 E2levels previously have been implied in
the exacerbation of mood symptoms (5–7, 9, 11), the lack of
negative mood induction in this study is somewhat surprising.
Furthermore, lower E2levels 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
Depression and anxiety scores for the two study groups during the different phases of the IVF-ET cycle.
Psychometric testProtocol (group)Baseline T0
Long ? short
Long ? short
Long ? short
Long ? short
Long ? short
32.46 ? 7.57
30.61 ? 8.46
32.34 ? 8.58
34.56 ? 9.06
34.32 ? 9.74
36.23 ? 9.44
34.36 ? 11.87
STAI40.54 ? 8.51
38.15 ? 9.94
39.68 ? 8.95
42.37 ? 10.63
43.71 ? 12.27
45.7 ? 10.88
44.10 ? 12.87
BSI-depression0.53 ? 0.45
0.41 ? 0.54
0.55 ? 0.54
0.60 ? 0.60
0.57 ? 0.63
0.61 ? 0.66
0.56 ? 0.61
BSI-anxiety0.71 ? 0.59
0.63 ? 0.59
0.72 ? 0.78
0.76 ? 0.69
0.80 ? 0.66
0.83 ? 0.76
0.85 ? 0.77
BSI-GSI0.51 ? 0.43
0.43 ? 0.41
0.57 ? 0.53
0.62 ? 0.58
0.55 ? 0.48
0.59 ? 0.55
0.57 ? 0.58
Note: Values are expressed as mean ? SD. BSI ¼ Derogatis brief symptoms inventory; BSI-GSI ¼ Derogatis brief symptoms inventory–global severity index;
CESD ¼ center for epidemiologic studies depression scale; STAI ¼ spielberger’s state anxiety inventory.
Bloch. Correspondence. Fertil Steril 2011.
Bloch et al.
Vol. 95, No. 1, January 2011
prevention of mood disorders (18). This argument has consider- Download full-text
able biologic support because E2significantly affects multiple
brain systems including memory, synaptic density, and serotonin
and norepinephrine neurotransmission (19–21).
reproductive-related mood disorders does not support this hypoth-
esis. The prevalence of depression is high in women in reproduc-
tive 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 relativelylow incidence
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 E2per se that underlie the emergence of depres-
sion in women, but rather their cyclicity (27).
theclinical and naturalhistory ofseveral
state that induces negative mood but the rapidity and magnitude of
changeinGSlevels.Because inthisparadigm GnRH-aisadminis-
tered 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
tic 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 in-
teraction 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 treat-
ment cycle. This elevation may be related to a nonspecific buildup
of stress resulting from the emotional complexity of the procedure.
ings 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 deci-
sion on the basis of individual-tailored treatment priorities rather
than on the risk of the possible emotional outcome.
Acknowledgments: The authors thank Mrs. Yael Shmueli and Mrs. Adel
Alon from the IVF unit for their help in recruitment and management of
1. KeeBS,Jung BJ,Lee SH.A study onpsychological
strain in IVF patients. J Assist Reprod Genet
2. Beaurepaire J, Jones M, Thiering P, Saunders D,
Tennant C. Psychosocial adjustment to infertility
and its treatment: male and female responses at
different stages of IVF/ET treatment. J Psychosom
3. Olivius C, Friden B, Borg G, Bergh C. Why do
treatment? A cohort study. Fertil Steril 2004;81:
4. Shalev E, Leung PC. Gonadotropin-releasing
hormone and reproductive medicine. J Obstet
Gynaecol Can 2003;25:98–113.
5. Patten SB, Barbui C. Drug-induced depression:
a systematic review to inform clinical practice.
Psychother Psychosom 2004;73:207–15.
6. Henzl MR, Corson SL, Moghissi K, Buttram VC,
Berqvist C, Jacobson J. Administration of nasal
nafarelin as compared with oral danazol for
endometriosis. A multicenter double-blind com-
parative clinical trial. N Engl J Med 1988;318:
7. Erickson LD, Ory SJ. GnRH analogues in the
treatment of endometriosis. Obstet Gynecol Clin
North Am 1989;16:123–45.
8. Schmidt PJ, Steinberg EM, Negro PP, Haq N,
Gibson C, Rubinow DR. Pharmacologically induced
hypogonadism and sexual function in healthy young
women and men.
9. Warnock JK, Bundren JC, Morris DW. Depressive
symptoms associated with gonadotropin-releasing
hormone agonists. Depress Anxiety 1998;7:171–7.
10. Warnock JK, Bundren JC, Morris DW. Depressive
mood symptoms associated
suppression. Fertil Steril 2000;74:984–6.
11. Ku ¨pker W, Felberbaum RE, Krapp M, Schill T,
Malik E, Diedrich K. Use of GnRH antagonists in
the treatment of endometriosis. Reprod Biomed
12. Toren P, Dor J, Mester R, Mozes T, Blumensohn R,
Rehavi M, et al. Depression in women treated with
a gonadotropin-releasing hormone agonist. Biol
13. Derogatis LR, Melisaratos N. The Brief Symptom
Inventory: an introductory report. Psychol Med
14. Spielberger CD, Gorsuch RL, Lushene RE. Test
manual for the State-Trait Anxiety Inventory. Palo
Alto (CA): Consulting Psychologists Press, 1970.
15. Spielberger CD, Gorsuch RL, Lushene R, Vagg PR,
Jacobs GA. Manual for the state-trait inventory.
Palo Alto (CA): Consulting Psychologists Press,
16. Radloff LS. The CES-D Scale: a self-report depres-
sion scale for research in the general population.
J Applied Psychol Measurement 1977;1:385–401.
17. Pandya R, Metz L, Patten SB. Predictive value of
the CES-D in detecting depression among candi-
dates for disease-modifying multiple sclerosis treat-
ment. Psychosomatics 2005;46:131–4.
18. Young EA, Midgley AR, Carlson NE, Brown MB.
Alteration in the hypothalamic-pituitary-ovarian
axis in depressed women. Arch Gen Psychiatry
19. McEwen BS, Alves SE. Estrogen actions in the
central nervous system. Endocr Rev 1999;20:
20. Rubinow DR, Schmidt PJ, Roca CA. Estrogen-
serotonin interactions: implications for affective
regulation. Biol Psychiatry 1998;44:839–50.
21. Weizman A, Morgenstern H, Rehavi M. Up-
regulatory effect of triphasic oral contraceptive on
platelet 3H-imipramine binding sites. Psychiatry
22. Schmidt PJ, Nieman L, Danaceau MA, Tobin MB,
Roca CA, Murphy JH, et al. Estrogen replacement
in perimenopause-related depression: a preliminary
report. Am J Obstet Gynecol 2000;183:414–20.
23. Freeman EW, Sammel MD, Lin H, Nelson DB.
Associations of hormones and menopausal status
with depressed mood in women with no history of
depression. Arch Gen Psychiatry 2006;63:375–82.
24. Cohen LS, Soares CN, Vitonis AF, Otto MW,
Harlow BL. Risk for new onset of depression
during the menopausal transition: the Harvard
study of moods and cycles. Arch Gen Psychiatry
25. Halbreich U. Gonadal hormones, reproductive age,
and women with depression. Arch Gen Psychiatry
26. Schmidt PJ, Rubinow DR. Sex hormones and mood
in the perimenopause. Ann N Y Acad Sci
menarche to menopause: exploring the underlying
biology of depression in women experiencing
28. Gavin NI, Gaynes BN, Lohr KN, Meltzer-Brody S,
Gartlehner G, Swinson T. Perinatal depression:
a systematic review of prevalence and incidence.
Obstet Gynecol 2005;106:1071–83.
Fertility and Sterility?