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Reproductive Steroid Regulation of Mood and Behavior

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ABSTRACT

In this article, we examine evidence supporting the role of reproductive steroids in the regulation of mood and behavior in women and the nature of that role. In the first half of the article, we review evidence for the following: (i) the reproductive system is designed to regulate behavior; (ii) from the subcellular to cellular to circuit to behavior, reproductive steroids are powerful neuroregulators; (iii) affective disorders are disorders of behavioral state; and (iv) reproductive steroids affect virtually every system implicated in the pathophysiology of depression. In the second half of the article, we discuss the diagnosis of the three reproductive endocrine‐related mood disorders (premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression) and present evidence supporting the relevance of reproductive steroids to these conditions. Existing evidence suggests that changes in reproductive steroid levels during specific reproductive states (i.e., the premenstrual phase of the menstrual cycle, pregnancy, parturition, and the menopause transition) trigger affective dysregulation in susceptible women, thus suggesting the etiopathogenic relevance of these hormonal changes in reproductive mood disorders. Understanding the source of individual susceptibility is critical to both preventing the onset of illness and developing novel, individualized treatments for reproductive‐related affective dysregulation. © 2016 American Physiological Society. Compr Physiol 6:1135‐1160, 2016e.

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Figure 1. Figure 1. Seventy‐two hours of culture of rat cortical neurons with 100 nm progesterone has opposite effects on neurite length [assessed after staining with microtubule associated protein‐2 (MAP2)] in neurons from male and female animals. The top panel shows cortical neurons stained with MAP2 in male (top) and female (bottom) untreated control rats (left) and those treated with progesterone (right). The bottom panel is a bar graph showing neurite length in male (blue) and female (red) untreated control rats (solid) and those treated with progesterone (striped). Neurite length is greater in female animals compared with males in the absence of progesterone, whereas the opposite is true following exposure to progesterone (L. Zhang et al., unpublished data). ***P < 0.001.
Figure 2. Figure 2. Synthetic pathways for the steroid hormones progesterone, estradiol, and allopregnanolone, reproduced with permission from (). Note that the same enzymes have multiple actions in the hormone cascade.
Figure 3. Figure 3. The hypothalamic‐pituitary‐gonadal (HPG) axis. The hypothalamus secretes GnRH, which acts on the pituitary gland. In response, the pituitary gland releases the gonadotropins LH and FSH. LH and FSH stimulate the ovaries to produce estrogen and progesterone. Depending on the menstrual cycle phase, estrogen and progesterone provide either positive or negative feedback to the hypothalamus and pituitary.
Figure 4. Figure 4. Recurrence of sadness in women with premenstrual syndrome during estradiol or progesterone add‐back in the context of GnRH agonist‐induced ovarian suppression, reproduced with permission from (). Ten women with premenstrual syndrome and 15 control women had minimal mood symptoms while receiving leuprolide acetate (a GnRH agonist). In contrast, the women with premenstrual syndrome but not the controls had a significant increase in sadness during the administration of either estradiol or progesterone. Values are the means (±SE) of the seven daily scores on the sadness scale of the Daily Rating Form () for each of the 8 weeks preceding hormone replacement (leuprolide alone) and during the 4 weeks of estradiol (plus leuprolide) and progesterone (plus leuprolide) replacement. A score of 1 indicates that they symptom was not present, and a score of 6 indicates that it was present in the extreme. P = 0.003 for interaction of treatment condition, diagnostic group, and week.
Figure 5. Figure 5. PET and fMRI activation in a multimodal imaging study of women with PMDD and a comparison group of women, reproduced with permission from (). Panel A shows the between‐group differences in activation using PET and fMRI. Regions in which patients had greater activation than comparison subjects are shown in pink. Panel B shows the correlations between Global Assessment of Functioning Scale (GAF) scores and activation in patients using PET and fMRI. Regions in which these two measures were negatively correlated (the greater the overactivation, the more severe impairment indicated by GAF scores) are shown in blue.
Figure 6. Figure 6. Mean scores on the Cornell Dysthymia Scale before and after estrogen and progesterone replacement in eight women with a history of postpartum depression and eight healthy comparison women, reproduced with permission from (). The significant difference between baseline and hormone withdrawal periods in the group with a history of postpartum depression (P < 0.01) is denoted by the symbol (*).
Figure 7. Figure 7. Abnormal maternal behaviors in GABAA receptor δ‐subunit‐deficient mice, reproduced with permission from (). Panel on right shows that decreased survival of pups born to GABAA receptor δ‐subunit‐deficient (Gabrd+/− and Gabrd−/−) mice is reduced by including a GABAA receptor δ‐subunit‐selective agonist (THIP) in drinking water. Panel on left shows that pups born to Gabrd+/− and Gabrd−/− mice but reared by a surrogate wild‐type mother immediately following birth had an increase in survival compared with wild‐type pups reared by Gabrd+/− and Gabrd−/− surrogate mothers immediately following birth.
Figure 8. Figure 8. The STRAW +10 staging system for reproductive aging in women, reproduced with permission from (). FMP, final menstrual period.


Figure 1. Seventy‐two hours of culture of rat cortical neurons with 100 nm progesterone has opposite effects on neurite length [assessed after staining with microtubule associated protein‐2 (MAP2)] in neurons from male and female animals. The top panel shows cortical neurons stained with MAP2 in male (top) and female (bottom) untreated control rats (left) and those treated with progesterone (right). The bottom panel is a bar graph showing neurite length in male (blue) and female (red) untreated control rats (solid) and those treated with progesterone (striped). Neurite length is greater in female animals compared with males in the absence of progesterone, whereas the opposite is true following exposure to progesterone (L. Zhang et al., unpublished data). ***P < 0.001.


Figure 2. Synthetic pathways for the steroid hormones progesterone, estradiol, and allopregnanolone, reproduced with permission from (). Note that the same enzymes have multiple actions in the hormone cascade.


Figure 3. The hypothalamic‐pituitary‐gonadal (HPG) axis. The hypothalamus secretes GnRH, which acts on the pituitary gland. In response, the pituitary gland releases the gonadotropins LH and FSH. LH and FSH stimulate the ovaries to produce estrogen and progesterone. Depending on the menstrual cycle phase, estrogen and progesterone provide either positive or negative feedback to the hypothalamus and pituitary.


Figure 4. Recurrence of sadness in women with premenstrual syndrome during estradiol or progesterone add‐back in the context of GnRH agonist‐induced ovarian suppression, reproduced with permission from (). Ten women with premenstrual syndrome and 15 control women had minimal mood symptoms while receiving leuprolide acetate (a GnRH agonist). In contrast, the women with premenstrual syndrome but not the controls had a significant increase in sadness during the administration of either estradiol or progesterone. Values are the means (±SE) of the seven daily scores on the sadness scale of the Daily Rating Form () for each of the 8 weeks preceding hormone replacement (leuprolide alone) and during the 4 weeks of estradiol (plus leuprolide) and progesterone (plus leuprolide) replacement. A score of 1 indicates that they symptom was not present, and a score of 6 indicates that it was present in the extreme. P = 0.003 for interaction of treatment condition, diagnostic group, and week.


Figure 5. PET and fMRI activation in a multimodal imaging study of women with PMDD and a comparison group of women, reproduced with permission from (). Panel A shows the between‐group differences in activation using PET and fMRI. Regions in which patients had greater activation than comparison subjects are shown in pink. Panel B shows the correlations between Global Assessment of Functioning Scale (GAF) scores and activation in patients using PET and fMRI. Regions in which these two measures were negatively correlated (the greater the overactivation, the more severe impairment indicated by GAF scores) are shown in blue.


Figure 6. Mean scores on the Cornell Dysthymia Scale before and after estrogen and progesterone replacement in eight women with a history of postpartum depression and eight healthy comparison women, reproduced with permission from (). The significant difference between baseline and hormone withdrawal periods in the group with a history of postpartum depression (P < 0.01) is denoted by the symbol (*).


Figure 7. Abnormal maternal behaviors in GABAA receptor δ‐subunit‐deficient mice, reproduced with permission from (). Panel on right shows that decreased survival of pups born to GABAA receptor δ‐subunit‐deficient (Gabrd+/− and Gabrd−/−) mice is reduced by including a GABAA receptor δ‐subunit‐selective agonist (THIP) in drinking water. Panel on left shows that pups born to Gabrd+/− and Gabrd−/− mice but reared by a surrogate wild‐type mother immediately following birth had an increase in survival compared with wild‐type pups reared by Gabrd+/− and Gabrd−/− surrogate mothers immediately following birth.


Figure 8. The STRAW +10 staging system for reproductive aging in women, reproduced with permission from (). FMP, final menstrual period.
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Crystal Edler Schiller, Sarah L. Johnson, Anna C. Abate, Peter J. Schmidt, David R. Rubinow. Reproductive Steroid Regulation of Mood and Behavior. Compr Physiol 2016, 6: 1135-1160. doi: 10.1002/cphy.c150014