NTP‐CERHR Expert Panel Report on the reproductive and developmental toxicity of fluoxetine

Hines, Ronald N.; Adams, Jane; Buck, Germaine M.; Faber, Willem; Holson, Joseph F.; Keszler, Martin; McMartin, Kenneth E.; Segraves, Robert; Singer, Lynn T.; Sipes, I. G.; Williams, Paige L.

doi:10.1002/bdrb.20014

Cited by 27 publications

(30 citation statements)

References 195 publications

(509 reference statements)

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“…Some investigators report improvement after chronic fluoxetine treatment while others report continued sexual dysfunction [17]. When the female rat's estrous cycle was monitored, we found resumption of both vaginal cyclicity and behavioral receptivity after 15 to 16 days of fluoxetine treatment [40].…”

Section: Introductionmentioning

confidence: 59%

“…A reported undesirable side effect of fluoxetine, as well as other selective serotonin reuptake inhibitors (SSRIs), is a high incidence of sexual dysfunction [8,15,28]. Although such sexual dysfunction occurs in both genders, more experimental emphasis has been placed on identifying the responsible mechanisms in males than in females [17]. Yet, as much as 32% of female patients may experience SSRI-*Corresponding author Department of Biology, Texas Woman's University, Denton, TX 76204, Phone: 940-898-2356, FAX: 940-898-2382.edu.…”

Section: Introductionmentioning

confidence: 99%

“…The mechanisms responsible for such drug-induced sexual dysfunction in females have been difficult to identify, perhaps due to the complexity of the female reproductive cycle and the number of neural and endocrine loops involved [2,9]. Nevertheless, most investigators have assumed that female sexual dysfunction occurs independent of a primary disturbance of the neuroendocrine events that normally contribute to sexual motivation and satisfaction [17]. However, we reported recently that daily treatment with 10 mg/kg fluoxetine disrupted both the female rat's estrous cycle (as monitored by the female's vaginal smear) and sexual behavior [40].…”

Section: Introductionmentioning

confidence: 99%

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Subchronic treatment with fluoxetine attenuates effects of acute fluoxetine on female rat sexual behavior

et al. 2008

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These experiments were designed to evaluate the hypothesis that fluoxetine-induced sexual dysfunction in female rats derived from disruption of neuroendocrine events that normally facilitate sexual behavior. If so, exogenous hormonal priming to ovariectomized rats should eliminate fluoxetine's effect. Ovariectomized rats were subchronically treated with 10 mg/kg fluoxetine or distilled/deionized water vehicle for 9 consecutive days. On the 8 th day of treatment, rats were primed with 10 μg estradiol benzoate followed 48 hr later with 500 μg progesterone. In a pretest for sexual behavior on the 10 th day, there was no difference between subchronic treatments. Sexual receptivity was again monitored 30 min after injection on the 10 th day (acute treatment) with distilled/deionized water, 10 mg/kg fluoxetine or 20 mg/kg fluoxetine. Thereafter, the female's behavior was monitored for 20 min in a male preference procedure. After the acute treatment in rats subchronically treated with water, fluoxetine (10 or 20 mg/kg) significantly reduced both lordosis frequency and quality and reduced (but not significantly) time spent with the male. In rats subchronically treated with fluoxetine, the lordosis-inhibiting effect of an acute injection with fluoxetine was significantly attenuated relative to that of the subchronically water-treated rats. In contrast to expectation, subchronic treatment with fluoxetine increased, rather than reduced, the relative time females spent near the male. Activity, as measured by center crossings, and grooming were also reduced by subchronic treatment with fluoxetine. KeywordsSSRI; sexual motivation; lordosis; subchronic IntroductionFluoxetine (Prozac®) is frequently prescribed for depression as well as for a variety of other disorders such as premenstrual dysphoria, anxiety, anorexia and bulemia which are more prevalent in females than in males [4,19,22,33]. A reported undesirable side effect of fluoxetine, as well as other selective serotonin reuptake inhibitors (SSRIs), is a high incidence of sexual dysfunction [8,15,28]. Although such sexual dysfunction occurs in both genders, more experimental emphasis has been placed on identifying the responsible mechanisms in males than in females [17]. Yet, as much as 32% of female patients may experience SSRI-*Corresponding author Department of Biology, Texas Woman's University, Denton, TX 76204, Phone: 940-898-2356, FAX: 940-898-2382.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. [32]. The mechanisms responsible for such drug-induced sexual dysfunction in females have been difficult to identify,...

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Section: Introductionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Subchronic treatment with fluoxetine attenuates effects of acute fluoxetine on female rat sexual behavior

et al. 2008

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“…NIH-PA Author Manuscript NIH-PA Author Manuscript dysfunction in females is well recognized, the responsible mechanisms have not been identified; but a fluoxetine-induced disturbance of the hypothalamic-pituitary-gonadal (HPG) system has been implicated [25,51,58,63,64]. In contrast to a plethora of animal studies directed toward SSRI-induced sexual dysfunction in males [25], in fewer reports has the female been emphasized [16,35,47,51,60,63,65]; and in even fewer have both vaginal and behavioral estrus been examined after daily treatment with fluoxetine [35,63].…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…This was a significant observation since it had been generally assumed that fluoxetine-induced female sexual dysfunction occurred independent of drug-induced modification of the HPG axis controlling estrous cyclicity. According to the NTP-CERHR Expert Panel Report in 2004, "The data in female rats are sufficient to qualitatively demonstrate that fluoxetine treatment with 10 mg/kg bw/day by s.c. or i.p injection results in altered estrous behavior and sexual receptivity, but has no effect on estrous cycle length" [25].Since concurrent vaginal and behavioral estrus have been examined in only two reports [35,63], it is important to identify explanations for the contrasting findings. In the following manuscript, we investigate one such potentially important difference between the two studies.…”

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confidence: 99%

Daily male exposure attenuates estrous cycle disruption by fluoxetine

Sarkar

Hiegel

Maswood

et al. 2008

Behavioural Brain Research

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Fluoxetine (Prozac®) produces sexual dysfunction in a substantial number of patients. In the few animal studies designed to address this sexual dysfunction in females, data have been inconsistent. Some investigators report that the drug disrupts sexual behavior without affecting the estrous cycle while we have reported robust effects of fluoxetine on the estrous cycle. The current studies were designed to initiate examination of procedural differences that may account for these contradictory outcomes. In the first experiment, intact, regularly cycling female rats were injected daily for 10 days with 10 mg/kg fluoxetine (intraperitoneally) or vehicle. Male-exposed, fluoxetine-or vehicle-treated rats were housed in a room with males and placed for 5 min/day into a male's cage. Other fluoxetinetreated females were housed in a room separate from males. In the second experiment, this protocol was repeated for 20 days and an additional group of females were exposed to male bedding for 5 min/day. Without male exposure, fluoxetine rapidly disrupted vaginal estrus and sexual receptivity so that approximately 50% of the rats failed to show vaginal estrus during the first 5 days; and the majority of the rats had a blocked cycle by 10 days of treatment. With male exposure, these reproductive effects were attenuated. The majority of rats cycled normally during the first 5 days of treatment and more than half cycled throughout the experiment. Loss of behavioral receptivity occurred even when normal estrous cyclicity was present. Although exposure to the male's bedding may have delayed the onset of estrous cycle disruption, five min daily exposure to a male's bedding did not prevent the disruptive effects of fluoxetine. These findings are consistent with evidence that fluoxetine's effect on female sexual dysfunction may result, in part, from the drugs' disruption of the hypothalamic-pituitary-gonadal axis. However, the data also evidence dissociation between the effects of fluoxetine on vaginal and behavioral estrus. These findings may also explain why different laboratories have reported the presence or absence of estrous cycle disturbances following daily treatment with fluoxetine. KeywordsSSRIs; intact rats; sexual behavior; pheromones; progesterone; estrus INTRODUCTIONSelective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac®), are effective in the treatment of depression [32,66] but produce sexual dysfunction in a substantial number of patients [12,19,38,39,55,59]. Although the high prevalence of SSRI-induced sexual *Corresponding author: Department of Biology, Texas Woman's University, Denton, TX 76204, Phone: 940-898-2356, FAX: 940-898-2382.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that durin...

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