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Depression in women treated with a gonadotropinreleasing hormone agonist
Depression in Women Treated with a GonadotropinReleasing Hormone Agonist Paz Toren, Jehoshua Dor, Roberto Mester, Tamar Mozes, Rachel Blumensohn, Moshe Rehavi, and Abraham Weizman K e y W o r d s : Depression, gonadotropin-releasing h o r m o n e agonist (GnRH-a), gonadorelin, decapeptyl BIOL PSYCHIATRY 1 9 9 6 ; 3 9 : 3 7 8 - 3 8 2
Introduction Gonadotropin-releasing-hormone (GnRH) is a hypothalamic hormone that controls the formation and release of gonadotropins from the pituitary gland (Matsuo et al 1971). GnRH and its synthetic analogues, when given continuously, were shown to induce a reversible state of hypogonadotropic hypogonadism (Belchetz et al 1978). GnRH agonists (GnRH-a) have a wide variety of clinical applications for estrogen- and testosteronedependent diseases or conditions, which benefit from the hypogonadotropic hypogonadism state induced by the agonists-e.g., in the treatment of endometriosis and polycystic ovary disease (Freude et al 1988; Shaw 1992) and in the treatment protocol of in vitro fertilization (IVF) (Dor et al 1990). Clinical studies reported depression-like side effects of GnRH-a treatment, including hot flushes, transient headaches, decrease in libido, mild insomnia, chronic fatigue, and depressed mood (Henzl 1988; Erickson and Ory 1989). These were generally attributed a priori to the hypoestrogenism temporarily induced by the GnRH-a. Upon reviewing the literature, no studies were found evaluatFrom the Ness-Ziona Mental Health Center; Sackler Faculty of Medicine, Tel-Aviv University (PT, RM, TM, RB); Sheba Medical Center, Tel-Hashomer; Sackler Faculty of Medicine, Tel-Aviv University (JD); Geha Psychiatric Hospital and Felsenstein Medical Research Center and Beilinson Medical Center, Petah Tiqva; Sackler Faculty of Medicine, Tel-Aviv University (AW); and the Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University (MR), Tel-Aviv, Israel. Address reprint requests to Paz Toren, M.D., Tel-Aviv Community Mental Health Center, 9 Hatzvi St., Ramat Hatayassim, Tel-Aviv, Israel 67197. Received November 30, 1994; revised June 27, 1995.
© 1996 Society of Biological Psychiatry
ing the prevalence, magnitude, duration, and characteristics of the above-mentioned depression-like symptoms that occur in patients under treatment with GnRH-a. The aim of the present study was to evaluate the emergence of depression and anxiety in women undergoing IVF with pretreatment with the GnRH-a decapeptyl.
Method Subjects Twenty-nine consecutive women due to undergo treatment at the IVF Unit participated in the study. Of these, 14 were randomly assigned to the decapeptyl group and 15 to the control group. The research protocol was approved by the Institutional Human Investigation Committee. The study was conducted as an openlabel trial, on an informed consent basis. According to the requirements of the Institutional Human Investigation Committee, the women were warned that the IVF treatment could induce dysphoria. The investigators were not blind to group assignment. Exclusion criteria were previous or current depressive symptomatology or any major psychiatric disorder. All women underwent a semistructured interview by a psychiatrist, using the Schedule for Affective Disorders and Schizophrenia (SADS-L) (Endicott and Spitzer 1978) to rule out any past or present psychiatric disorders. Age range of the subjects in the decapeptyl group was 23-42 years (mean = 32.1, SD = 6.5), and of the controls, 22-42 years (mean = 33.0, SD = 5.7). 0006-3223/96/$15.00 SSDI 0006-3223(95)00473-4
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Treatment Protocol DECAPEPrVL GROUP: All women in the decapeptyl group received GnRH-a D-Trp6-LHRH microcapsules (Decapeptyl, 3.2 mg CR, Ferring Ltd., Sweden) on day 3 of the menstrual cycle. Beginning on day 15 of the menstrual cycle, human menopausal gonadotropin (hMG) (Pergonal, Teva Pharmaceutical Industries Ltd., Israel), 225 IU/day, was administered. Follow-up by sonography and measurements of daily blood estrogen (E2) levels determined the day of human chorionic gonadotropin (hCG) (Chorigon, Teva Pharmaceutical Industries Ltd., Israel), 10,000 IU administration. Thirty-six hours after hCG administration, oocytes were retrieved by ultrasound-guided transvaginal aspirations (Dor et al 1990).
CONTROLGROUP: The control group underwent the same procedure, except for the GnRH-a administration. Thus, hMG (225 IU/day) was administered from cycle day 3 onward, until the day of hCG injection. Thirty-six hours
after hCG administration, oocytes were retrieved by ultrasound-guided transvaginal aspirations.
Study Design The decapeptyl and control subjects were assigned four and three time points, respectively, for the various clinical evaluations and blood sampling. Clinical psychologic rating scales included the Hamilton rating scales for depression (21-item) (HAM-D) (Hamilton 1967) and anxiety (HAM-A) (Hamilton 1959) and the subjective visual analogue scales (10 cm) for depression (VAS-D) and anxiety (VAS-A) (McCormack et al 1988). Blood samples were collected at the time of the clinical interview. Estradiol, progesterone, prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and cortisol levels were determined using radioimmunoassay (RIA) technique. Study points of the decapeptyl group included baseline values, hypogonadal phase (11 days after the decapeptyl injection), peak follicular phase, and peak luteal phase [9 days after embryo transfer, beyond the bioavailability of decapeptyl (t 1/2 = 4-5 weeks)]. Time points of the control group included all but the second, hypogonadal, phase.
Table 1. Decapeptyl Group: Fluctuations in Hormonal Levels and in Psychometric Parameters by Study Points (by Time) Study Points
Hormones/Parameters
17 [3 E2 a (pg/mL) SEM X Progesteroneb (ng/mL) SEM J( Prolactin (ng/mL) SEM
1 Baseline Values 54.1 10.8 0.43 0.03
2 Hypogonadal Phase
3 Follicular Phase
4 Luteal Phase
32.5 5.3
1380.0 202.0
472.3 251.3
101.8
<0.001
12.6 3.3
86.6
<0.001
<0.001
0.32 0.05
0.67 0.11
F3,39
p
12.6 2.7
12.5 2.3
23.9 2.4
36.5 4.3
22.70
5.1 0.6
6.8 0.5
8.3 1.4
5.4 0.4
3.36
LH (mlU/mL) SEM J( FSH (mlU/mL) SEM
4.6 0.5
2.4 0.4
10.2 0.8
1.1 0.1
58.15
<0.001
11.3 1.4
17.0 2.0
16.1 2.2
23.0 2.6
14.29
<0.001
Cortisol (txg%) SEM J~ HAM-D points SEM
3.1 1.0
9.4 1.7
9.0 1.7
5.6 1.6
7.5
<0.001
J( HAM-A points SEM
3.9 0.8
7.4 1.3
7.8 1.4
5.8 1.2
4.22
<0.01
J~ VAS-D (cm) SEM
2.4 0.4
4.9 0.8
2.9 0.4
3.2 0.7
3.69
<0.02
)( VAS-A (cm) SEM
2.9 0.5
3.8 0.7
3.8 0.4
4.0 0.9
0.60
NS
<0.03
LH - luteinizing hormone; FSH = follicle-stimulating hormone; HAM-D = Hamilton Rating Scale for Depression; HAM-A = Hamilton Rating Scale for Anxiety; VAS-D = Visual Analogue Scale for Depression; VAS-A = Visual Analogue Scale for Anuety. ~The repeated-measures ANOVA for estrogen (E2) was performed using log m transformations of E2 because the values of E2 were not normally distributed. bSimilarly, progesterone (P) was analyzed using log m (100 × P).
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Table 2. Control Group: Fluctuations in Hormonal Levels and in Psychometric Parameters by Study-Points (by Time) Study Points 1 Baseline
Hormones/Parameters
Values
2 Follicular Phase
3 Luteal Phase
17 13 E2a (pg/mL) SEM
52.4 4.6
1928.7 273.6
144.7 27.7
)~ Progesterone b (ng/mL) SEM
0.39 0.04
0.99 0.19
F2,28
10.5 1.56
p
137.9
<0.001
106.4
<0.001
12.2 1.3
22.8 3.3
22.7 2.9
9.36
<0.001
,Y LH (mlU/mL) SEM
7.1 0.6
20.7 3.4
20.7 3.4
13.63
<0.001
,~ FSH (mlU/mL) SEM
5.8 0.4
8.6 0.5
2.5 0.3
57.69
<0.001
,~ Cortisol (mcg%) SEM
13.2 0.9
18.9 1.2
20.1 1.6
15.71
<0.001
3~ HAM-D points SEM
2.4 0.6
3.8 0.8
3.6 0.6
1.78
NS
.~ HAM-A points SEM
4.0 0.9
4.4 0.9
3.8 0.6
0.20
NS
.k" VAS-D (cm) SEM
2.0 0.4
2.7 0.4
2.8 0.4
1.49
NS
2~ VAS-A (cm) SEM
3.4 0.4
4.1 0.5
4.2 0.6
1.74
NS
Prolactin (ng/mL) SEM
LH = luteinizing hormone; FSH = follicle-stimulating hormone; HAM-D = Hamilton Rating Scale for Depression; HAM-A = Hamilton Rating Scale for Anxiety; VAS-D = Visual Analogue Scale for Depression; VAS-A = Visual Analogue Scale for Anxiety. aThe repeated-measures ANOVA for estrogen (E2) was performed using loglo transformations of E2 because the values of E2 were not normally distributed. bSimilarly, progesterone (P) was analyzed using log~ 0 (100 × P).
Statistical Analysis Analysis of variance with repeated measures (ANOVA-RM) was used to determine the differences between the two groups and to evaluate the effect of time. A post-hoc paired t test was performed on the difference between estradiol levels of the decapeptyl group at baseline and hypogonadal phases.
Results Baseline values (two groups) were not significantly different for age, duration of infertility, number of previous IVF treatments, number of previous hMG treatments, hormonal levels (except for LH), and psychometric evaluations (t = 0.01-1.76, df = 27, p > 0.05) (Tables 1 and 2). On comparing the decapeptyl and the control groups along the study points for the decapeptyl effect on each of the mood parameters, a statistically significant interaction was found between them for the HAM-D (F = 4.76, df = 2,54, p < 0.02) and HAM-A (F = 3.79, df = 2,54, p < 0.03) scores. Closer investigation of the decapeptyl group only (Figure 1, Table 1) showed a significant increase in depression levels (as measured by the HAM-D) at the hypogonadal and follicular phases as
compared to baseline (F = 7.5, df = 3,39, p < 0.001). An increase, albeit less marked, was also noted in VAS-D (F = 3.69, df = 3,39, p < 0.02); however, none of the women met the
'~ ~ ii/3aseliho t~ i-ii~Po0o haaai -c3F0,icui~ ~ i.iiieai ........
Dec-,peptyl i Control Xe!
i
!
! HAM-D HAM-A VAS-D
VAS-A
HAM-D HAM-& VAS-D
VAS-A
Figure 1. Fluctuations of psychometric parameters in the decapeptyl and control groups (by study points: baseline values, hypogonadal phase, peak follicular phase, peak luteal phase). **p < 0.001; *p < 0.02; repeated-measures analysis of variance.
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DSM-III-R criteria for major depression. An increase in anxiety levels (HAM-A) was noted as well in the decapeptyl group at the hypogonadal and follicular phases as compared to baseline (F = 4.22, df = 3,39, p < 0.02); nevertheless, no statistically significant increase was detected for VAS-A, the subjective measure of anxiety. In the control group (Figure 1, Table 2), no statistically significant increase was noted in either depression or anxiety at any of the time points. The interaction between the decapeptyl and control groups along the study points for the endocrine parameters was statistically significant for estrogen, prolactin, LH, FSH, and cortisol (F = 3.39-6.34, df = 2,54 p < 0.05), while there was no significant interaction for progesterone. Gonadotropin treatment caused highly significant increases in estradiol, progesterone, prolactin, and cortisol levels in the decapeptyl group (14.29 <- F --< 101.8, df = 3,39 p < 0.001) and the control (9.36 -< F --< 137.9, df = 2,28 p < 0.001) group, as expected, at the follicular and luteal phases (Tables 1, 2). Decapeptyl administrationcaused a decrease of 40% in estradiol levels at the hypogonadal phase of the decapeptyl group (t = 3.35, df = 13, p = 0.005).
Discussion The major finding of the study is that pretreatment with GnRH-a, as part of an IVF protocol, is associated with a substantial increase in depression level in euthymic subjects. A rise in anxiety level was also demonstrated, but was not manifested on the subjective scales. The anxiety symptoms may have been mainly an expression of the known overlap between depression and anxiety symptomatology (Snaith and Turpin 1990). The hypogonadism caused by decapeptyl at the hypogonadal phase coincided with the increase in depression and anxiety levels. Previous reports have demonstrated an upregulatory effect of estradiol on the serotonin transporter (Weizman et al 1988), known to play a major role in the pathogenesis of depression (Van Praag 1984). Thus, the hypoestrogenism caused by GnRH-a might be associated with dysregulated serotonergic neurotransmission leading to depression. The depression, however, persisted at the peak follicular phase of the decapeptyl
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group, despite the marked increase in estradiol levels caused by hMG administration. Thus, hypoestrogenism might have induced the depression, which then took its own course irrespective of the subsequent changes in estradiol levels. Alternatively, GnRH-a might also affect depression or anxiety through its central activity--directly or by mediators other than the pituitary or ovarian hormones (Bancroft et al 1987). Previous studies have demonstrated a bidirectional saturable transport of GnRH across the blood-brain barrier (Barrera et al 1991); thus, the possibility of a central depressogenic effect of GnRH-a, unrelated to hypoestrogenism, cannot be disregarded. GnRH-a can sometimes diminish mood symptoms related to menstrual cycle (premenstrual syndrome), probably by abolishing ovarian cyclicity (Bancroft et al 1987; West and Hillier 1994). The factor of abolishing ovarian cyclicity may, in this specific syndrome, counteract the dysphoric changes of the GnRH-a treatment. The present study assessed the impact of GnRH-a treatment on mood for a short-term protocol involving GnRH-a for IVF patients. The results, however, may have broader implications because of the longer-term use of this medication in the treatment of endometriosis, uterine fibroids, and other conditions. It would be interesting to investigate how enduring the dysphoric effect is in chronic use of GnRH-a. The present preliminary study raised the possibility that GnRH-a may induce depression in euthymic subjects; however, despite the marked increase in depression and anxiety levels, the maximal scores on the Hamilton scales were quite modest, and none of the women developed full-blown major depression. Nevertheless, the possible deleterious effect of GnRH-a on mood should not be ignored and merits further investigation in a double blind, placebo-controlled design. In order to isolate the directneural from the hormonal factors as the possible mechanism of GnRH-a-induced depression, the effect of estrogen-replacement therapy during the hypogonadal phase on the emergence of depression and anxiety should be evaluated.
The authors thank Mrs. Pearl Lilos for statistical analysis.Special thanks to Mrs. Judith Ben-Ezzer, RNBA, IVF Nurse Coordinator, for her invaluableclinical observationand assistance.
References Bancroft J, Boyle H, Warner P, Fraser HM (1987): The use of an LHRH agonist, buserelin, in the long-term management of premenstrual syndromes. Clin Endocrinol 27:171. Barrera CM, Kastin AJ, Fasold MB, Banks WA (1991): Bidirectional saturable transport of LHRH across the blood-brain barrier. Am J Physiol 261(3, pt 1):E312-E318. Belchetz PE, Plant TM, Nakai Y, Keogh EJ, Knobil E (1978): Hypophyseal responses to continuous and intermittent delivery of hypothalamic gonadotropin releasing hormone. Science 202:631-633. Dor J, Ben-Shlomo I, Lipitz S, Levran D, Etchin A, Rudak E, Mashiach S (1990): Ovarian stimulation with gonadotropinreleasing hormone (GnRH) analogue improves the in vitro fertilization (IVF) pregnancy rate with both transvaginal and
laparoscopic oocyte recovery. J In Vitro Fert Embryo Trans 7:351-354. Endicott J, Spitzer RL (1978): A diagnostic interview: The Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry 35:837-844. Erickson LD, Ory SJ (1989): GnRH analogues in the treatment of endometriosis. Obstet Gynecol Clin North Am 16:123-145. Freude G, Artner B, Leodotler S (1988): First experiences and results with the GnRH-agonist decapeptyl CR in the treatment of PCO patients. Gynecol Endocrinol 2(suppl 2):390. Hamilton M (1959): The assessment of anxiety states by rating. Br J Med Psychol 32:50-55. Hamilton M (1967): Development of a rating scale for primary depressive illness. Br J Social Clin Psychol 6:278-296.
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Henzl MR (1988): Gonadotropin-releasing hormone (GnRH) agonists in the management of endometriosis: a review. Clin Obstet Gynecol 31:840-856. Matsuo H, Baba Y, Nair RM, Arimura A, Schally AV (1971): Structure of the porcine LH and FSH-releasing hormone: I. The proposed amino acid sequence. Biochem Biophys Res Commun 43:1334-1335. McCormack HH, Home DJ de L, Sheather S (1988): Clinical applications of visual analogue scales: a critical review. Psychol Med 18:1007-1019. Shaw RW (1992): Treatment of endometriosis. Lancet 340: 1267-1271. Snaith RP, Turpin G (1990): Clinical anxiety states. In: Peck DF,
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Shapiro CM (eds), Measuring Human Problems--A Practical Guide. Chichester: John Wiley & Sons, pp 67-89. Van Praag HM (1984): Depression, suicide and serotonin metabolism in the brain. In Post RM, Ballenger JC (eds), Neurobiology of Mood Disorders. Baltimore: Williams & Wilkins Co, pp 601-618. Weizman A, Morgenstern H, Rehavi M (1988): Up-regulatory effect of triphasic oral contraceptive on platelet 3H-Imipramine binding sites. Psychiatry Res 23:23-27. West CP, Hillier H (1994): Ovarian suppression with the gonadotropin-releasing hormone agonist goserelin (zoladex) in the management of the premenstrual tension syndrome. Hum Reprod 9:1058-1063.
Introduction Gonadotropin-releasing-hormone (GnRH) is a hypothalamic hormone that controls the formation and release of gonadotropins from the pituitary gland (Matsuo et al 1971). GnRH and its synthetic analogues, when given continuously, were shown to induce a reversible state of hypogonadotropic hypogonadism (Belchetz et al 1978). GnRH agonists (GnRH-a) have a wide variety of clinical applications for estrogen- and testosteronedependent diseases or conditions, which benefit from the hypogonadotropic hypogonadism state induced by the agonists-e.g., in the treatment of endometriosis and polycystic ovary disease (Freude et al 1988; Shaw 1992) and in the treatment protocol of in vitro fertilization (IVF) (Dor et al 1990). Clinical studies reported depression-like side effects of GnRH-a treatment, including hot flushes, transient headaches, decrease in libido, mild insomnia, chronic fatigue, and depressed mood (Henzl 1988; Erickson and Ory 1989). These were generally attributed a priori to the hypoestrogenism temporarily induced by the GnRH-a. Upon reviewing the literature, no studies were found evaluatFrom the Ness-Ziona Mental Health Center; Sackler Faculty of Medicine, Tel-Aviv University (PT, RM, TM, RB); Sheba Medical Center, Tel-Hashomer; Sackler Faculty of Medicine, Tel-Aviv University (JD); Geha Psychiatric Hospital and Felsenstein Medical Research Center and Beilinson Medical Center, Petah Tiqva; Sackler Faculty of Medicine, Tel-Aviv University (AW); and the Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University (MR), Tel-Aviv, Israel. Address reprint requests to Paz Toren, M.D., Tel-Aviv Community Mental Health Center, 9 Hatzvi St., Ramat Hatayassim, Tel-Aviv, Israel 67197. Received November 30, 1994; revised June 27, 1995.
© 1996 Society of Biological Psychiatry
ing the prevalence, magnitude, duration, and characteristics of the above-mentioned depression-like symptoms that occur in patients under treatment with GnRH-a. The aim of the present study was to evaluate the emergence of depression and anxiety in women undergoing IVF with pretreatment with the GnRH-a decapeptyl.
Method Subjects Twenty-nine consecutive women due to undergo treatment at the IVF Unit participated in the study. Of these, 14 were randomly assigned to the decapeptyl group and 15 to the control group. The research protocol was approved by the Institutional Human Investigation Committee. The study was conducted as an openlabel trial, on an informed consent basis. According to the requirements of the Institutional Human Investigation Committee, the women were warned that the IVF treatment could induce dysphoria. The investigators were not blind to group assignment. Exclusion criteria were previous or current depressive symptomatology or any major psychiatric disorder. All women underwent a semistructured interview by a psychiatrist, using the Schedule for Affective Disorders and Schizophrenia (SADS-L) (Endicott and Spitzer 1978) to rule out any past or present psychiatric disorders. Age range of the subjects in the decapeptyl group was 23-42 years (mean = 32.1, SD = 6.5), and of the controls, 22-42 years (mean = 33.0, SD = 5.7). 0006-3223/96/$15.00 SSDI 0006-3223(95)00473-4
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Treatment Protocol DECAPEPrVL GROUP: All women in the decapeptyl group received GnRH-a D-Trp6-LHRH microcapsules (Decapeptyl, 3.2 mg CR, Ferring Ltd., Sweden) on day 3 of the menstrual cycle. Beginning on day 15 of the menstrual cycle, human menopausal gonadotropin (hMG) (Pergonal, Teva Pharmaceutical Industries Ltd., Israel), 225 IU/day, was administered. Follow-up by sonography and measurements of daily blood estrogen (E2) levels determined the day of human chorionic gonadotropin (hCG) (Chorigon, Teva Pharmaceutical Industries Ltd., Israel), 10,000 IU administration. Thirty-six hours after hCG administration, oocytes were retrieved by ultrasound-guided transvaginal aspirations (Dor et al 1990).
CONTROLGROUP: The control group underwent the same procedure, except for the GnRH-a administration. Thus, hMG (225 IU/day) was administered from cycle day 3 onward, until the day of hCG injection. Thirty-six hours
after hCG administration, oocytes were retrieved by ultrasound-guided transvaginal aspirations.
Study Design The decapeptyl and control subjects were assigned four and three time points, respectively, for the various clinical evaluations and blood sampling. Clinical psychologic rating scales included the Hamilton rating scales for depression (21-item) (HAM-D) (Hamilton 1967) and anxiety (HAM-A) (Hamilton 1959) and the subjective visual analogue scales (10 cm) for depression (VAS-D) and anxiety (VAS-A) (McCormack et al 1988). Blood samples were collected at the time of the clinical interview. Estradiol, progesterone, prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and cortisol levels were determined using radioimmunoassay (RIA) technique. Study points of the decapeptyl group included baseline values, hypogonadal phase (11 days after the decapeptyl injection), peak follicular phase, and peak luteal phase [9 days after embryo transfer, beyond the bioavailability of decapeptyl (t 1/2 = 4-5 weeks)]. Time points of the control group included all but the second, hypogonadal, phase.
Table 1. Decapeptyl Group: Fluctuations in Hormonal Levels and in Psychometric Parameters by Study Points (by Time) Study Points
Hormones/Parameters
17 [3 E2 a (pg/mL) SEM X Progesteroneb (ng/mL) SEM J( Prolactin (ng/mL) SEM
1 Baseline Values 54.1 10.8 0.43 0.03
2 Hypogonadal Phase
3 Follicular Phase
4 Luteal Phase
32.5 5.3
1380.0 202.0
472.3 251.3
101.8
<0.001
12.6 3.3
86.6
<0.001
<0.001
0.32 0.05
0.67 0.11
F3,39
p
12.6 2.7
12.5 2.3
23.9 2.4
36.5 4.3
22.70
5.1 0.6
6.8 0.5
8.3 1.4
5.4 0.4
3.36
LH (mlU/mL) SEM J( FSH (mlU/mL) SEM
4.6 0.5
2.4 0.4
10.2 0.8
1.1 0.1
58.15
<0.001
11.3 1.4
17.0 2.0
16.1 2.2
23.0 2.6
14.29
<0.001
Cortisol (txg%) SEM J~ HAM-D points SEM
3.1 1.0
9.4 1.7
9.0 1.7
5.6 1.6
7.5
<0.001
J( HAM-A points SEM
3.9 0.8
7.4 1.3
7.8 1.4
5.8 1.2
4.22
<0.01
J~ VAS-D (cm) SEM
2.4 0.4
4.9 0.8
2.9 0.4
3.2 0.7
3.69
<0.02
)( VAS-A (cm) SEM
2.9 0.5
3.8 0.7
3.8 0.4
4.0 0.9
0.60
NS
<0.03
LH - luteinizing hormone; FSH = follicle-stimulating hormone; HAM-D = Hamilton Rating Scale for Depression; HAM-A = Hamilton Rating Scale for Anxiety; VAS-D = Visual Analogue Scale for Depression; VAS-A = Visual Analogue Scale for Anuety. ~The repeated-measures ANOVA for estrogen (E2) was performed using log m transformations of E2 because the values of E2 were not normally distributed. bSimilarly, progesterone (P) was analyzed using log m (100 × P).
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Table 2. Control Group: Fluctuations in Hormonal Levels and in Psychometric Parameters by Study-Points (by Time) Study Points 1 Baseline
Hormones/Parameters
Values
2 Follicular Phase
3 Luteal Phase
17 13 E2a (pg/mL) SEM
52.4 4.6
1928.7 273.6
144.7 27.7
)~ Progesterone b (ng/mL) SEM
0.39 0.04
0.99 0.19
F2,28
10.5 1.56
p
137.9
<0.001
106.4
<0.001
12.2 1.3
22.8 3.3
22.7 2.9
9.36
<0.001
,Y LH (mlU/mL) SEM
7.1 0.6
20.7 3.4
20.7 3.4
13.63
<0.001
,~ FSH (mlU/mL) SEM
5.8 0.4
8.6 0.5
2.5 0.3
57.69
<0.001
,~ Cortisol (mcg%) SEM
13.2 0.9
18.9 1.2
20.1 1.6
15.71
<0.001
3~ HAM-D points SEM
2.4 0.6
3.8 0.8
3.6 0.6
1.78
NS
.~ HAM-A points SEM
4.0 0.9
4.4 0.9
3.8 0.6
0.20
NS
.k" VAS-D (cm) SEM
2.0 0.4
2.7 0.4
2.8 0.4
1.49
NS
2~ VAS-A (cm) SEM
3.4 0.4
4.1 0.5
4.2 0.6
1.74
NS
Prolactin (ng/mL) SEM
LH = luteinizing hormone; FSH = follicle-stimulating hormone; HAM-D = Hamilton Rating Scale for Depression; HAM-A = Hamilton Rating Scale for Anxiety; VAS-D = Visual Analogue Scale for Depression; VAS-A = Visual Analogue Scale for Anxiety. aThe repeated-measures ANOVA for estrogen (E2) was performed using loglo transformations of E2 because the values of E2 were not normally distributed. bSimilarly, progesterone (P) was analyzed using log~ 0 (100 × P).
Statistical Analysis Analysis of variance with repeated measures (ANOVA-RM) was used to determine the differences between the two groups and to evaluate the effect of time. A post-hoc paired t test was performed on the difference between estradiol levels of the decapeptyl group at baseline and hypogonadal phases.
Results Baseline values (two groups) were not significantly different for age, duration of infertility, number of previous IVF treatments, number of previous hMG treatments, hormonal levels (except for LH), and psychometric evaluations (t = 0.01-1.76, df = 27, p > 0.05) (Tables 1 and 2). On comparing the decapeptyl and the control groups along the study points for the decapeptyl effect on each of the mood parameters, a statistically significant interaction was found between them for the HAM-D (F = 4.76, df = 2,54, p < 0.02) and HAM-A (F = 3.79, df = 2,54, p < 0.03) scores. Closer investigation of the decapeptyl group only (Figure 1, Table 1) showed a significant increase in depression levels (as measured by the HAM-D) at the hypogonadal and follicular phases as
compared to baseline (F = 7.5, df = 3,39, p < 0.001). An increase, albeit less marked, was also noted in VAS-D (F = 3.69, df = 3,39, p < 0.02); however, none of the women met the
'~ ~ ii/3aseliho t~ i-ii~Po0o haaai -c3F0,icui~ ~ i.iiieai ........
Dec-,peptyl i Control Xe!
i
!
! HAM-D HAM-A VAS-D
VAS-A
HAM-D HAM-& VAS-D
VAS-A
Figure 1. Fluctuations of psychometric parameters in the decapeptyl and control groups (by study points: baseline values, hypogonadal phase, peak follicular phase, peak luteal phase). **p < 0.001; *p < 0.02; repeated-measures analysis of variance.
Brief Reports
DSM-III-R criteria for major depression. An increase in anxiety levels (HAM-A) was noted as well in the decapeptyl group at the hypogonadal and follicular phases as compared to baseline (F = 4.22, df = 3,39, p < 0.02); nevertheless, no statistically significant increase was detected for VAS-A, the subjective measure of anxiety. In the control group (Figure 1, Table 2), no statistically significant increase was noted in either depression or anxiety at any of the time points. The interaction between the decapeptyl and control groups along the study points for the endocrine parameters was statistically significant for estrogen, prolactin, LH, FSH, and cortisol (F = 3.39-6.34, df = 2,54 p < 0.05), while there was no significant interaction for progesterone. Gonadotropin treatment caused highly significant increases in estradiol, progesterone, prolactin, and cortisol levels in the decapeptyl group (14.29 <- F --< 101.8, df = 3,39 p < 0.001) and the control (9.36 -< F --< 137.9, df = 2,28 p < 0.001) group, as expected, at the follicular and luteal phases (Tables 1, 2). Decapeptyl administrationcaused a decrease of 40% in estradiol levels at the hypogonadal phase of the decapeptyl group (t = 3.35, df = 13, p = 0.005).
Discussion The major finding of the study is that pretreatment with GnRH-a, as part of an IVF protocol, is associated with a substantial increase in depression level in euthymic subjects. A rise in anxiety level was also demonstrated, but was not manifested on the subjective scales. The anxiety symptoms may have been mainly an expression of the known overlap between depression and anxiety symptomatology (Snaith and Turpin 1990). The hypogonadism caused by decapeptyl at the hypogonadal phase coincided with the increase in depression and anxiety levels. Previous reports have demonstrated an upregulatory effect of estradiol on the serotonin transporter (Weizman et al 1988), known to play a major role in the pathogenesis of depression (Van Praag 1984). Thus, the hypoestrogenism caused by GnRH-a might be associated with dysregulated serotonergic neurotransmission leading to depression. The depression, however, persisted at the peak follicular phase of the decapeptyl
BIOLPSYCHIATRY 1996;39:378-382
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group, despite the marked increase in estradiol levels caused by hMG administration. Thus, hypoestrogenism might have induced the depression, which then took its own course irrespective of the subsequent changes in estradiol levels. Alternatively, GnRH-a might also affect depression or anxiety through its central activity--directly or by mediators other than the pituitary or ovarian hormones (Bancroft et al 1987). Previous studies have demonstrated a bidirectional saturable transport of GnRH across the blood-brain barrier (Barrera et al 1991); thus, the possibility of a central depressogenic effect of GnRH-a, unrelated to hypoestrogenism, cannot be disregarded. GnRH-a can sometimes diminish mood symptoms related to menstrual cycle (premenstrual syndrome), probably by abolishing ovarian cyclicity (Bancroft et al 1987; West and Hillier 1994). The factor of abolishing ovarian cyclicity may, in this specific syndrome, counteract the dysphoric changes of the GnRH-a treatment. The present study assessed the impact of GnRH-a treatment on mood for a short-term protocol involving GnRH-a for IVF patients. The results, however, may have broader implications because of the longer-term use of this medication in the treatment of endometriosis, uterine fibroids, and other conditions. It would be interesting to investigate how enduring the dysphoric effect is in chronic use of GnRH-a. The present preliminary study raised the possibility that GnRH-a may induce depression in euthymic subjects; however, despite the marked increase in depression and anxiety levels, the maximal scores on the Hamilton scales were quite modest, and none of the women developed full-blown major depression. Nevertheless, the possible deleterious effect of GnRH-a on mood should not be ignored and merits further investigation in a double blind, placebo-controlled design. In order to isolate the directneural from the hormonal factors as the possible mechanism of GnRH-a-induced depression, the effect of estrogen-replacement therapy during the hypogonadal phase on the emergence of depression and anxiety should be evaluated.
The authors thank Mrs. Pearl Lilos for statistical analysis.Special thanks to Mrs. Judith Ben-Ezzer, RNBA, IVF Nurse Coordinator, for her invaluableclinical observationand assistance.
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