Posted by jrbecker76 on July 22, 2008, at 0:01:12
In reply to know anything about elevated prolactin??, posted by obsidian on July 9, 2008, at 18:54:53
> it's not from hypothyroidism
> not from antipsychotics
> no pituitary tumor detected from MRI
> no pregnancy, no breastfeeding
>
> the level is over 50
>
> could it be a stress reaction??increased prolactin is an extremely common side effect of most serotonergic medications.
Abstract
Purpose: To evaluate endocrine profile and hypothalamic-pituitary-testis (HPT) axis in male depressed patients with selective serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction (SDF).
Materials and Methods: Eighty-six fertile depressed male patients with SSRI-induced SDF, aged 18 to 50 years, were enrolled in the study (group 1). Sixty-two age-matched depressed fertile patients who currently receive one of the SSRIs but without SDF (group 2), and 68 age-matched healthy fertile men who had never received a psychiatric diagnosis (group 3) served as controls. Pretreatment evaluation included history and physical examination and International Index of Erectile Function. Two blood samples were drawn from each subject at 20-minute intervals for the determination of the resting levels of the following hormones: luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, prolactin, and estradiol. The HPT axis was also assessed using the gonadotropin-releasing hormone test.
Results: The prevalence of hormonal abnormalities in groups 1, 2, and 3 were 83.7% (72), 51.6% (32), and 11.8% (7), respectively (P = 0.001 vs group 1 and 0.007 vs group 2). Compared with normal controls, the subjects taking SSRIs had significantly lower serum levels of LH, FSH, and testosterone. In addition, there were significantly decreased LH and FSH responses to gonadotropin-releasing hormone test in groups 1 and 2 compared with normal controls. Of patients in groups 1 and 2, 68 (79.1%) and 27 (43.5%) had elevated serum levels of prolactin (P = 0.0001 vs group 1 and 0.001 vs group 2).
Conclusions: Most depressed subjects taking SSRIs with and without SDF had diminished HPT axis function. This should be replicated in further studies.
The selective serotonin reuptake inhibitors (SSRIs) have become first-line agents for the treatment of many mood and anxiety disorders.1 Although the SSRIs have a generally more favorable side effect profile than the older classes of antidepressants, sexual dysfunction (SDF) is a frequent and disturbing adverse event of SSRIs that influences a patient's desire to continue long-term antidepressant treatment.2-4 The main neurotransmitters involved are serotonin (5-HT), acetylcholine, noradrenaline (NA), and dopamine (DA). Increased 5-HT activity on the serotonin type 2 (5-HT2) and type 3 (5-HT3) receptors inhibiting dopaminergic systems, inhibition of [alpha]-adrenergic and cholinergic receptors in genitourinary tract, or decreased nitric oxide (NO) production 5,6 are proposed mechanisms for development of SDF. Sexual dysfunction occurs in 58% to 73% of patients taking SSRIs.4 About 5% of the UK adult population take an antidepressant 7,8 with similar prescribing rates in the United States.9
Furthermore, long-term administration of antidepressants can alter receptor number and function for a variety of monoamine systems, with [beta]-adrenergic and serotonin (5-HT2) receptors being predominantly susceptible in this regard.10,11 The control of gonadotropin-releasing hormone (GnRH) secretion depends on several neurotransmitters, such as 5-HT, NA, DA, and NO. It has been previously reported that serotoninergic innervation for medial preoptic area stimulates whereas 5-HT in the medial basal hypothalamus inhibits luteinizing-hormone (LH) secretion.12 The actual effects of SSRIs in hypothalamic-pituitary-testis (HPT) axis and related hormones have not been identified yet. To our knowledge, this is the first study addressing HPT axis in depressed patients taking SSRIs.
MATERIALS AND METHODSEighty-six fertile depressed men aged 18 to 50 years (mean age 32 years; range, 27-49 years) meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (text revision; American Psychiatric Association, 1994) criteria for unipolar depression and SDF that emerged during the SSRI treatment were recruited for the study (group 1). Subjects had to have a score of more than or equal to 17 on the 17-item Hamilton Rating Scale for Depression.13 All of these subjects received one of the following antidepressants: citalopram, escitalopram, fluoxetine, paroxetine, or sertraline. Sixty-two age-matched depressed fertile patients who currently receive one of the above mentioned SSRIs as treatment modality but without any alterations in sexual function (group 2) and 68 age-matched healthy fertile men who had never received a psychiatric diagnosis (group 3) served as controls. All of the subjects had fathered at least 1 child. After procedures and possible side effects were explained to the patients, all subjects gave their written informed consent before entering the study, which was conducted in accordance with the Declaration of Helsinki. The Human Ethics Committee of Urology and Nephrology Research Center approved the study protocol.
Inclusion or Exclusion CriteriaPatients who met the following criteria were included: patients regularly taking an SSRI for 12 months or more experiencing SSRI-induced SDF for 6 months or more if they were under age 50 and patients who reported their SDF began after initiation of treatment with their current antidepressant. The patient had to be in a stable relationship with his wife for at least the previous 6 months and had a possible sexual intercourse equal or greater than one per week, which could lead to orgasm, and is willing to discuss their sexual functioning with the investigator. None of the patients had received other treatment of SDF before the start of the study.
Excluded were those with an organic cause of SDF, including anatomic abnormalities, genital infection, and neurologic disorder; diabetes mellitus; major physical illness; alcohol, drug, or substance abuse; use of psychotropic or neuroleptic medication (other than SSRIs); use of any medication known to cause SDF such as anticholinergic agents, antihistamines (H1 or H2 blockers), and antihypertensives; and serious relationship problems. Patients meeting study criteria had their medical and sexual histories and demographic information recorded.
EvaluationsAll patients underwent preliminary assessment, including medical and sexual history, physical examination, and structured interview diagnostic of mental and physical disorders. Self-administration International Index of Erectile Function 14 was used as an assessment measure. The International Index of Erectile Function is a 15-item questionnaire that assesses the 5 domains of sexual function: erectile function is assessed by the responses to questions 1 to 5 and 15, orgasmic function questions 9 and 10, sexual desire questions 11 and 12, intercourse satisfaction questions 6 through 8, and overall satisfaction questions 13 and 14. Three domains of sexual function were assessed using this questionnaire: erectile function, orgasmic function, and sexual desire. Each question was scored on a scale from 1 (almost never or never) to 5 (almost always or always). Scores less than 50% of maximum achievable score in each 3 domains (erectile function, orgasmic function, and sexual desire) were considered as SDF in that domain. All patients were asked to indicate their sexual satisfaction on a scale of 0 to 5 as proposed by Kim and Paick,15 with 0 being extremely dissatisfied and 5 being extremely satisfied.
By ultrasonography, transverse and longitudinal images of each testis were obtained, and length, width, and height measurements were done using electronic calipers. Testicular volumes were computed using the empirical formula of Lambert: length × width × height × 0.71.
Two early morning blood samples were drawn from each subject at 20-minute intervals for the determination of the resting levels of the following hormones: LH, follicle-stimulating hormone (FSH), prolactin (PRL), testosterone, and estradiol (E2). All hormones were assayed by commercial radioimmunoassay kits. All of these commercial kits had been used previously with interassay and intraassay variations of less than 10%. All basal and stimulated hormone measurements were performed in the same assay. Reference ranges for LH, FSH, testosterone, E2, and PRL were 4 to 23 IU/L, 2 to 19 IU/L, 10 to 35 nmol/L, 43 to 122 pmol/L, and 92 to 697 pmol/L, respectively.
The HPT axis was also assessed using the GnRH test. After taking basal blood samples, 100 µg gonadotropin-releasing hormone analog (GnRHa) was administered by intravenous bolus. Subjects remained supine throughout, and blood was sampled for FSH, LH, testosterone, and PRL at -15, 0, 20, 40, 60, and 120 minutes after injection.
Statistical AnalysisThe null hypothesis was that depressed patients taking SSRIs and healthy men did differ on the HPT axis function. A significance of 0.05 (2-tailed) was required to reject the null hypothesis. A sample size of 180 subjects (minimum 60 in each group) was calculated to give 80% power to detect a significant difference in each of the measured variables at [alpha] = 0.05. Sample homogeneity was determined according to procedures described elsewhere, in which heterogeneity is present if the between-groups variance (t2) is greater than zero and/or the within-groups variance test ([chi]2) is significant. Data are presented as means ± SD. Statistical analysis was performed by using unpaired Welch corrected t test to compare data among the various groups. The Wilcoxon signed rank sum test was used to assess the extent of variations in hormone levels after GnRHa administration. The nonparametric Mann-Whitney test was also used to compare the LH response to LHRH of subjects and normal controls at various times points. The areas under the curve of hypophyseal hormone response to LHRH were also compared using the nonparametric Mann-Whitney test. Linear regression was used to analyze the correlation between peak and area of LH response to GnRHa with serum testosterone level. A 2-tailed P < 0.05 was considered to indicate a statistically significant difference. Statistical analysis was performed using the Statistical Package for the Social Sciences for Windows (version 10.0; SPSS, Inc, Chicago, Ill) and SAS (version 6.4; SAS Institute Inc, Cary, NC).
RESULTS
Patient Disposition or DemographicsMean patient age was 32.0 years (range, 27-49 years) in group 1, 33.0 years (range, 28-49 years) in group 2, and 32.4 years (range, 28-49 years) in group 3 (all P = 0.1). The study and control groups were similar in demographic and clinical characteristics. The type of SDF was erectile dysfunction in 46 patients (53.5%), reduced libido in 25 patients (29.1%), and delayed ejaculation or an ejaculation in 15 patients (17.4%). Of the patients, 15 (17.4%), 9 (10.5%), 32 (37.2%), 12 (14%), and 18 (20.9%) had received citalopram, escitalopram, fluoxetine, paroxetine, and sertraline, respectively. The sexual satisfaction rates of the patients with SDF were as follows: 12 patients (14%) satisfied, 24 patients (27.9%) moderately satisfied, and 50 patients (58.1%) dissatisfied.
LH and FSHThe mean for LH and FSH in depressed subjects with SDF was significantly lower than the mean for depressed patients without SDF and the mean for normal controls. The mean for normal control group did differ significantly from the means for the group 2 (Table 1).
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[Email Jumpstart To Image] TABLE 1. Serum Hormonal Profile in Participants
TestosteroneThe mean serum testosterone level in depressed subjects with SDF (9.1 ± 4.4 nmol/L) was significantly lower than the mean for depressed subjects without SDF (12.1 ± 5.4 nmol/L; P = 0.02) and the mean for normal controls (16.4 ± 6.1 nmol/L; P = 0.008). The mean for group 2 was significantly lowerthan the mean for group 3 (P = 0.02; Table 1).
ProlactinThe mean for normal controls (352 ± 126 pmol/L) was significantly lower than the means for groups 1 and 2 (both P = 0.01; Table 1).
EstradiolThe basal serum E2 values did not differ significantly between the 3 groups (Table 1).
Hormonal Abnormalities PatternThe depressed subjects with SDF had significantly higher hormonal abnormalities than the depressed subjects without SDF and normal controls (Table 2).
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[Email Jumpstart To Image] TABLE 2. Prevalence of Hormonal Abnormalities
Type of AntidepressantThere was no statistically significant correlation between SDF and type of antidepressant use (P = 0.07).
Testicular VolumeMean testicular volumes as measured by ultrasonography were 24.4 ± 3.2, 25.1 ± 3.1, and 24.8 ± 3.3 mL in groups 1, 2, and 3, respectively. There was no significant difference in testis volume between the 3 groups (all P = 0.1).
GnRH TestOf the patients taking SSRIs with and without SDF, 49 (57%) and 28 (45.2%) had an abnormal GnRHa response. The injection of GnRHa did not yield a significant increase in FSH and LH levels in the patients taking SSRIs compared with normal controls. In normal healthy volunteers, FSH increased about 2-fold, from an average of 6.7 IU/L before the injection to 13.2 IU/L after (P = 0.001). In the depressed patients with and without SDF, FSH rose from 2.4 and 4.8 to 3.6 and 7.1IU/L, respectively (P = 0.03; Fig. 1). The area under the curve of FSH responses to GnRHa for subjects taking SSRIs is significantly lower than that of normal controls (mean ± SD, 369 ± 169 vs 2624 ± 1174 IUmin/L; P = 0.001). In groups 1 and 2, LH increased from 3.3 and 4.8 to 5.8 and 7.2 IU/L, respectively (P = 0.03; Fig. 1). In the normal subjects, LH increased about 4-fold, from an average of 5.9 IU/L to 24.1 IU/L (P = 0.001 vs group 1 and 0.01 vs group 2). Again, the area under the curve of LH responses to GnRHa for subjects taking SSRIs is significantly lower than that of normal controls (mean ± SD, 407 ± 185 vs 2568 ± 1121 IUmin/L; P = 0.001). There was a significant correlation between the serum levels of LH and FSH and their responses to GnRHa (P = 0.02). Of depressed patients with SD, 17 (19.8%) and 20 (23.3%) had delayed and normal LH responses to GnRHa, respectively.
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[Email Jumpstart To Image] FIGURE 1. Mean baseline and GnRH-stimulated FSH (top) and LH (bottom) levels in depressed patients with SDF and without SDF and normal controls.
DISCUSSIONThe present study demonstrated that patients treated with SSRIs had gonadotropin secretion impairments. This was more prominent in those patients with SDF. This is to our knowledge the first study addressing endocrine profile and HPT axis in patients taking SSRIs. These sexual side effects can considerably reduce compliance with medication 16 and can lead to less effective treatment of the primary psychiatric disorder.
We did not find significant differences in endocrine abnormalities between SSRIs. The mechanisms of SSRI-induced SDF are largely inferential, derived in part from in vitro models. The control of GnRH secretion depends on several neurotransmitters, such as 5-HT, NA, DA, and NO.17 The actual role of 5-HT in gonadotropin secretion has not been identified yet. Serotonin in the medial basal hypothalamus inhibits LH secretion.12 Among the depressed subjects with SDF included in this study, 20% were responders to GnRHa administration. In this study, we chose to assess hormones that have important roles in sexual function. SSRIs evaluated in this study were drugs known as those that tend to cause SDF.
An interesting finding made in this study was that although patients in group 2 did not have SDF, they had apparent hormonal abnormalities but in lesser extend. Therefore, low-serum LH, FSH, and testosterone did not seem to be the sole possible mechanisms of SDF. Serotonergic, dopaminergic, and cholinergic-adrenergic neurotransmitter systems have all been implicated in SDF, as have the limbic system and the specific hormones.18,19 In different studies, SDF has been attributed to increased 5-HT activity on the 5-HT2 and type 5-HT3 receptors inhibiting dopaminergic systems, inhibition of [alpha]-adrenergic and cholinergic receptors in genitourinary tract, or reduced NO production.6,7
It should also be noted that due to different genotypes in different individuals, 5-HT metabolization might also be different. Therefore, in subjects taking SSRIs, the required time to achieve special levels of sex hormones varies. Perhaps, subjects in group 2 needed more time to achieve identical serum hormonal levels with group 1. Therefore, duration and type of medication are important determinant factors for hormonal abnormalities. In our study, patients taking SSRIs had significant hyperprolactinemia. Hyperprolactinemia is an undesirable effect of SSRI use 20 and can cause SDF.21
Although more research is needed to determine the exact mechanism that leads to SDF in individuals taking SSRIs, the present study suggests that alteration in HPT axis may play an important role in developing SDF. A sample consisting of more patients could have allowed us to detect differences more adequately in some hormonal variables. Further work is needed to test this and other related questions.
CONCLUSIONSIn conclusion, we report that SSRI-induced SDF was associated with disturbed and diminished HPT axis function. Many remain to be learned about the exact mechanism(s) of SSRI-induced SDF. Further studies are needed to shed light on the understanding and treatment of this understudied disorder.
ACKNOWLEDGMENTSThe author thanks Miss Saba Safarinejad for her assistance in the preparation of the manuscript. The efforts of the study coordinators, statistician, monitors, and nurses are sincerely appreciated. The investigator is indebted to the patients and controls who participated in this study without whom this study would not have been possible.
AUTHOR DISCLOSURE INFORMATIONThe author declares no funding or conflicts of interest.
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