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Perinatal Mood, Cognition and Hormones

Published on February 22, 2023

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While searching through old research files for an article I am writing on mitochondria and hormones, I stumbled upon the presentation notes for my thesis defense. I thought some of our readers might find them interesting. Although, I was not able to find the original PowerPoint presentation, I did find a later presentation that included my thesis and dissertation research, along with the some background information on neuroendocrinology. You can read my thesis here and/or the articles published from that research here and here. I added a few subheadings for readability, but otherwise, the presentation remains unchanged.

Perinatal hormones, mood, and cognition – 2007 from Hormones Matter

Perinatal Mood, Cognition, and Hormones

The purpose of this study was to identify the cognitive and emotional changes associated with pregnancy hormones both during pregnancy and postpartum and to identify early markers for perinatal mood dysfunction.

This research was based upon several physiological presumptions regarding pregnancy and postpartum. Conventional wisdom holds that during pregnancy reproductive hormones increase exponentially to support the pregnancy. It also posits that after delivery those levels decrease rapidly to below normally circulating levels and remain low until breastfeeding ceases and menstruation begins.

Animal research shows that many reproductive hormones are neuroactive and potently modulate numerous neurotransmitters systems. Given the large and sustained increased in such hormones followed by the precipitous decline, one would expect clear behavioral changes associated both with the elevated and diminished states of circulating hormones. We would also expect that the change from high hormone to low hormone state would mimic an addiction/withdrawal syndrome.

Numerous animal studies indicated that this was the case, but the connection between hormones and behavior in human studies was inconsistent and inconclusive for many reasons outlined in my research. The most important failing of previous research has been the lack of theory or evidence-based design. That is, not only has previous research failed to recognize, and hence, postulate neurosteroid/neurotransmitter mediated behaviors, but often failed to recognize the clearly articulated affective dysregulation presented regularly in clinical case research.

The question of which hormones modulate which neurotransmitters and to what behavioral consequences has not been asked, nor has the possibility that perinatal mood might be altered across several domains ever been addressed. Instead, most if not all, research focuses exclusively on progesterone and estradiol without so much as even speculating which neural circuits might be involved. Moreover, despite ample clinical evidence to the contrary, most research thus far measured and continues to measure only anhedonic depressive symptoms.

This study was different. Because extensive clinical case research revealed that perinatal mood was more often than not comprised of multiple syndromes of which depression was merely a part, I expanded the psychiatric domains measured to include assessment of 9 common psychiatric modalities and utilized a standardized and validated measure.

Additionally, previous studies measured only progesterone and/or estradiol. This study measured five hormones, progesterone, DHEAS, estrone, estradiol, estriol and testosterone. The timing of assessment in other studies has been inconsistent and again not obviously evidence based. With approximately, 70% of all cases of postpartum psychosis occurring in first two weeks post-delivery, I thought it was important to measure within that time frame to capture those changes. Since case reports reveal premorbid symptoms during late pregnancy, I also measured at 37 weeks of pregnancy.

This study utilized salivary assays to measure hormone levels and controlled time of day and food intake. All previous studies measured hormones at non-standardized times and did not control food intake. Hormones have diurnal rhythms, and food intake, particularly with salivary assays will comprise results.

But perhaps the most important difference between this and previous studies is that this study was designed, all instruments were selected and the timing of testing was determined, based upon the presumed neuromodulatory activity of these hormones and the predicted concomitant behaviors associated therein, using an addiction/withdrawal framework. Thus it was imperative to test in the immediate postpartum so as to capture changes before neurological and behavioral adaptation occur.

It’s All About GABA

Given these considerations, much of the study design was based upon progesterone’s capacity to modulate the GABA system.

Progesterone is a potent allosteric GABAa agonist and anxiolytic. However, chronically elevated progesterone becomes anxiogenic via its actions on receptor conformation. It was postulated that during the course of pregnancy, the women would be the beneficiaries of the progesterone’s anxiolytic actions, but that towards the end of the pregnancy, as receptor conformation changed, the GABAa receptor would become immune not only to progesterone’s actions but GABA’s actions as well with the net behavioral effect of increased anxiety.

Postpartum, when progesterone was withdrawn the lack of CNS GABA transmission would induce hyper-excitability across several CNS systems that would be expressed in elevated anxiety symptoms and mood lability.

Major Findings: It’s Not Progesterone or Estradiol and It’s Not Depression

What I didn’t know going into this study was that DHEAS also modulated GABAa but did so antagonistically. What I also didn’t know, and what is in fact the first major finding of this study, was that circulating DHEAS levels increased throughout pregnancy and postpartum. All previous research indicated that DHEAS increased over the first two trimesters, decreased during the third and returned to normal immediately proceeding delivery. This was not the case. Although I have only two test times, DHEAS levels were clearly very high at 37 weeks, and increased postpartum by an average of 34%. Indeed only 6 participants showed waning postpartum DHEAS levels.

Returning to the GABA hypothesis, as is now becoming clear, during most of the pregnancy progesterone positively modulates GABA transmission. Toward the end of pregnancy when progesterone levels presumably level off but are nonetheless at supra-physiological levels, the chronicity of exposure elicits conformational changes in the receptor making it unresponsive to progesterone and according to animal research unresponsive to benzodiazepines as well. Concurrently, DHEAS levels are increasing and are now blocking whatever limited GABA transmission exists. Parturition occurs, progesterone levels diminish by some 93% while DHEAS levels continue to increase. So now whatever remaining GABA binding sites are still available become blocked and CNS hyper-excitability ensues leading to the behavioral lability seen in almost all women during the first two weeks postpartum.

The behavioral sequelae of these rather dramatic physiological changes include increased anxiety, phobia, OCD, paranoia psychoticism, and importantly many physiological symptoms tapped by the somatization scale of the SCL-90R, particularly cardiovascular dysregulation, increased heart rate, respiration, sweating, etc.

Postpartum, even in asymptomatic women, that is the 80% of women who experience what is imprecisely called “baby-blues” is often marked by hyper-excitability and mood lability as much or more so that anhedonia and depression. This is with good reason given the neurochemical and physiological changes occurring as these hormones adapt to the non-pregnant state.

Thus, the second major finding in this study was that although depression was certainly present, it was by no means the sole determinant and I would argue not even the primary or causative factor in the observed mood dysregulation postpartum. This is really important because insofar as previous and indeed current research continues to focus on postpartum depression rather than perinatal mood more broadly, hundreds of thousands of women get misdiagnosed, under-diagnosed and inappropriately treated. The findings from this study indicate that not only do negative mood symptoms begin in late pregnancy but that the disorder itself is characterized as much by anxiety or positive type symptoms as it is by depressive and anhedonic type symptoms.

The third major finding of this study was the connection between late pregnancy and post-delivery hormones to negative mood. As was outlined in my research, the design of this study was very strongly based upon the neuromodulatory capacity of progesterone on the GABAa system. Results from this research indicate that progesterone was not correlated with negative mood and thus I was wrong about progesterone. Nevertheless, I was correct about GABA being a major player in perinatal mood dysregulation.

Recent research suggests that DHEAS is a potent GABAa antagonist similar to the drug picrotoxin. That is, it is capable of binding to a site deep within the receptor, thereby limiting GABA influx.

Given DHEAS’ influence on GABA, its increase late pregnancy and post-delivery, one would expect clear and consistent correlations between DHEAS levels and mood. That is exactly what I found. Pre-delivery DHEAS was correlated with paranoia and psychoticism.

Post delivery DHEAS was strongly and significantly correlated with just about every mood symptom measured by the SCL-90R including anxiety, phobia, paranoia, somatization, and the GSI. Recall that DHEAS levels increased an average of 34% and increased for all but of 6 of the women postpartum. In some women, those who had the most severe postpartum difficulties, DHEAS levels increased 2-4X pre-delivery levels.

Moreover, the fourth major finding from this research showed that pre-delivery testosterone was correlated not only with pre-delivery negative mood (phobia, psychoticism, somatization and GSI), but was correlated strongly and significantly with almost every negative mood symptom measured by the SCL-90R post-delivery as well, including anxiety, hostility, psychoticism, somatization, OCD, interpersonal sensitivity, depression and GS. And the correlation was negative. That means that diminished testosterone (amidst the presumably elevated levels of pregnancy) were correlated with increased negative symptoms. This is important for a number of reasons, not the least of which is its predictive possibilities, but it suggests that the adrenal androgens of which DHEAS and testosterone are key component are implicated in perinatal mood.

This is groundbreaking. It has never been addressed before in the literature. If we look at the biosynthesis of steroid hormones during pregnancy, we see that DHEAS is produced both by the fetal and maternal adrenals and is intra-converted in the placenta as well. Biologically, DHEAS is considered inactive, meaning that it must be converted to DHEA before other downstream hormones can be metabolized. DHEAS is storage component for DHEA. If more DHEA is converted to DHEAS, for whatever reason, then less downstream hormones-testosterone are synthesized. These are the results I found. Since I didn’t measure DHEA, I can only speculate, but these two factors in hormone synthesis appear to be altered and these alterations are related to the mood perinatal mood dysfunction. Future studies are needed to confirm these findings and determine their etiology but preliminarily these results open up an entirely different direction for future research that has yet to be addressed, the implications of which will be far-reaching.

Perinatal Cognitive Changes

The cognitive results from this study were no less impressive but not as easily interpreted because cognitive ability was not consistently linked to either mood or hormone data but was obviously impaired.

As a group, these women were educated with many having graduate degrees. The average estimated IQ was approximately 1 SD above the mean and might have been higher if complete testing had been performed. Most of these women worked outside the home in a professional capacity for the duration of their pregnancies, and yet when tested, showed significant memory and executive function deficits when compared to age and education matched normative data. The degree of impairment was striking, and quite frankly, unexpected.

In verbal memory measured by the CVLT-II, many percentile rankings were below the 20^th percentile. When testing these women, it became apparent how important semantic memory was, with those women recognizing the categories of words having little difficulty completing the task and probably skewing the data somewhat. However, for a large percentage of the women, there was absolutely no recognition of the categories inherent in the task and their ability to recall even a fraction of the words was hindered tremendously. The women also repeated words, in some cases 2 and 3 times during the course of a trial and recalled words that were not part the trial list.

On spatial memory tasks the deficits were no less obvious. As is exemplified by the CFT tasks, shown in the appendix of my thesis, the impairment was at least in part related to an inability to see the drawing as an entirety. If we look at these drawings closely, we see that in the copy phase, the core of the drawing, the rectangle is missing. That is, each section of the figure is drawn separately. This presents difficulties in encoding that will ultimately limit performance of the recall portion of the task. Again notice the piece meal quality of the figures in the recall task, with large portions of the figure completely missing. The examples illustrated here are representative of performance across participants.

The mood to cognition relationship was interesting if not paradoxical. Conventional wisdom would suggests that negative mood, particularly depression and anxiety would impair cognitive performance. This was not the case. Indeed depression actually improved performance.

The hormones to cognition relationships were no less confusing except that changes in DHEAS were correlated with poorer performance on the CVLT-II. Given the magnitude and direction of change in DHEAS levels this was consistent with the earlier results. Progesterone, was not correlated with mood symptoms but was correlated to both aspects of the design fluency task and the estrogens were correlated with a variety of task both pre and postpartum.

What was particularly interesting about this aspect of the research was that cognitive ability declined in many areas postpartum, but participants perceived themselves as having improved. The disconnect between perception and performance was clear almost across the board.

Finally, it may be that as in the case of other mental illnesses, cognitive functioning is not correlated with severity of symptoms but is associated with measures of therapeutic outcome such that higher premorbid functioning predicts one’s ability to function during and after an episode.

This possibility begs the question that if another group of women was tested having lower premorbid cognitive function and lower socio-economic status, would they have fared as well as the women in this study. That is, would their ability to withstand the physiological and consequent emotional/behavioral change associated with pregnancy and postpartum be comparable to the abilities of this group?

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The studies addressed here were published in 2007 as part of my PhD dissertation. This post was published on HM on November 29, 2018.

Framing the Pregnancy Postpartum Hormone Mood Debate

by Chandler Marrs, PhD

Published on June 17, 2013

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The two years beginning in late pregnancy and continuing post childbirth can be particularly difficult for many women. The risk of serious mental illness is significantly higher than at any other time in a woman’s life. More often than not, however, the mental health issues are attributed to the stress of becoming a mom and though hormones are often in the mix, the consensus about pregnancy and postpartum hormone-related mental health changes is more broad than specific, anecdotal than evidence based. The prevailing hypothesis suggests that puerperal mental illness, commonly referred to and investigated as postpartum depression, is not the result of endocrine pathophysiology, but rather a ‘maladaptive’ response to normal changes in reproductive hormones. In other words, having babies is a normal function, with normal hormone changes, ‘if you can’t handle it, there must be something wrong with you.’

The fact that there are no norms or even broad reference ranges established for pregnancy/postpartum hormone changes doesn’t seem to enter into many conversations (how can one reasonably say something is normal if it isn’t ever measured?); nor does the fact that ‘abnormal’ hormone changes could easily be causative in mental illness or the fact that ‘normal’ hormone changes, if large enough, such as during pregnancy and following childbirth are likely to impact mood, cognition and behavior in some fairly noticeable ways. Failing to recognize and prepare women and their families for the spectrum of the biochemically mediated mental health or mental status changes, whether they are ’normal’ or not, is just wrong and potentially dangerous. Many years ago, I set out to change that – to understand how the hormones of pregnancy and postpartum could affect mental health and cognition. What I found was fascinating, but first, a little (OK, a lot of) background.

Fundamental Precepts about Hormones and Behavior

All of my research begins with the basic proposition that hormones affect brain chemistry. We know from animal research that hormone receptors are located all over the brain (and the body for that matter), even in areas not responsible for reproduction. We also know that steroid hormones produced in the body, because they are lipid soluble, easily cross the blood-brain-barrier and bind to hormone and non-hormone receptors to change brain chemistry. And, we know that the brain can and does produce a full complement of steroid hormones by itself, having all of the necessary building blocks to synthesize hormones de novo or from scratch. Since the brain is the control center for mental health, cognition and indeed, everything, it stands to reason that because hormone activity is integral to brain chemistry, hormones are involved in mental health. Indeed, there are no biologically or even logically plausible reasons to remove hormones from any discussion of brain chemistry or subsequent changes in mental status. It just makes no sense.

Pregnancy and Postpartum Hormone Changes Mirror an Addiction Withdrawal Cycle

We see hints, sometimes rather loud hints, of the hormone-brain connection across a woman’s life cycle (puberty and menopause) and across the menstrual cycle, but these are often more gradual and less drastic biochemical changes than those of pregnancy and postpartum. During pregnancy, some hormones increase by over 1000 times their non-pregnant concentrations, only to drop immediately, to nothing or almost nothing following childbirth. Simultaneously, other hormones seem to increase following childbirth, thus, creating the complex chemical cocktail that is postpartum. With these enormous changes in biochemistry, it is truly remarkable that so few women experience difficulties.

From a pharmacological standpoint, the hormone changes across pregnancy and postpartum provide the perfect drug addiction-withdrawal model, where the drug use increases gradually but significantly over an extended period of time only to be eliminated cold turkey over a period of a couple days. From the brain’s standpoint, while there may be differences in specific reactions, there really is no difference, broadly speaking, between compensatory reactions it exhibits relative to increasing concentrations of a drug followed by its abrupt withdrawal and those it exhibits relative to increasing concentrations of hormones followed by abrupt withdrawal. The brain is going to get used to having certain concentrations of chemicals floating around and adapt accordingly. When those chemicals are removed, especially abruptly, there will be hell to pay in the withdrawal syndrome. How that withdrawal syndrome manifests will be contingent on the degree and pattern of biochemical change – which hormones or drug(s) are creating the problems, where and to what degree.

Consider alcohol versus heroin withdrawal as an example. Both withdrawal periods are horrible, but because each drug acts on different neurotransmitters within the brain, each withdrawal syndrome looks a little bit different. It is the same way with hormones. Each elicits a different biochemical reaction in the brain. Some hormones are sedatives, some are stimulants, some are direct, some are indirect; some have a whole bunch of receptors in areas of the brain that control memory, while others have receptors in the emotional centers of the brain. Without measuring the actual hormone changes associated with pregnancy and postpartum and the behavioral symptoms that ensue, there is no way to recognize or to treat a postpartum withdrawal syndrome or syndromes. And as many of you well know, hormone measurement in women’s health is all but ignored.

Pregnancy and Postpartum Mood Changes are Poorly Characterized

Perhaps because of our feminist tendencies (not wanting to admit that hormones affect our moods or our cognitive abilities), perhaps politics (blaming women) or perhaps just poor research (including that which does not consider the role of hormones in the diagnostic criteria), the standard nomenclature and diagnostic parameters for postpartum mental health issues are at best poorly defined and at worst completely incorrect.

According popular perspectives, the three classes of postpartum disease are the baby blues which is said to affect 80% of all new moms, postpartum depression that develops in 10-15% of women and postpartum psychosis, the rare condition that afflicts 1-2 per 1000 pregnant women. What does this mean? It looks like a progression of sadness that leads to psychosis. Is this what postpartum women experience? Well, not really, but the nomenclature stuck and was sufficiently correct that they could characterize some of the symptoms, in some of the women, to make using these terms a useful shorthand. However, because the symptoms associated with each of these conditions were never fully characterized appropriately, they have been repeatedly included or dis-included from diagnostic manuals with varying and even diametrically opposed diagnostic criteria depending upon the political winds of any given generation (the pitfalls of consensus based medicine).

Indeed, in the last iterations (IV, TR) of the DSM manual (the diagnostic bible for mental illness), postpartum was merely a time course specifier. That means, none of these conditions actually existed according to the diagnostic manual. There was no discrete illness or set of illnesses recognized as unique to the postpartum period, and certainly none connected to postpartum hormone changes. Depression or psychosis, if they happened to arise within 30 days of childbirth, was considered postpartum related. If these conditions developed during pregnancy or after the 30 day period, then they were not considered postpartum related. In effect, these conditions were just the normal, run-of-the-mill depression or psychosis. From a purely logical standpoint, it seems difficult to believe that the brain chemistry of a postpartum woman is in any way similar to the brain chemistry of teenager or menopausal, or other non-postpartum woman or to a male depressed or psychotic patient. If we believe that brain chemistry mediates behavior (and isn’t the entire medical-pharmaceutical establishment built on that presumption), why would we presume that radically different brain chemistries produce the same symptoms or behaviors? We wouldn’t.

So, on the one hand, we have popular terminology that has done wonders to bring awareness to the potential difficulties some women have following childbirth but whose terms were not consistent with the DSM criteria. On the other hand, we have DSM criteria that really didn’t recognize postpartum as unique condition, but only as a time-frame to be noted and neither set of diagnostic opportunities was based on evidence that truly considered specific hormones changes might impact brain chemistry. Sure, there has always been the tacit – it’s hormonal – and certainly, there has been hormone-mood research but attempting to delineate which hormones, in which women, relative to which symptoms and within what time frame has yet to be fully addressed. And, as one might imagine, it is difficult to bring another set of variables – hormones- into an already poorly defined disease space. Do we measure hormones related to blues, depression and psychosis or are we measuring something else entirely?

Where to Begin

When beginning a research career in area where the data are limited, one has a few choices – ‘don’t’ -being the first and most logical option; take the safe, career boosting-route of replicating someone else’s work or throw all previous assumptions in the garbage can and begin from scratch. Not being the wisest, of course, I chose the third option.

I had a couple operating assumptions. The first was and still is, that certain hormones affect certain neurotransmitters (we know this to be true from animal research). When we radically change the concentrations of those hormones, the behaviors associated with said neurotransmitters (and maybe even some we hadn’t thought of) would become apparent. Second, the symptoms that were expressed would be related to the particular pattern of hormone change – whatever that pattern may be. Third, the constellation of symptoms that arose would not likely not fall into the current diagnostic categories, but would cluster together in unique, and yet to be determined, ways. In other words, I believed that certain patterns would emerge based on animal research, but because there was so little human research and much of it was limited in scope, I was prepared for the fact that I was wrong. And I was wrong, in some ways, but that willingness to test more broadly and openly is what led to some pretty amazing discoveries.

How I Think about Perinatal Psychiatric Distress

Last bit of background, I promise. Notice that I said perinatal psychiatric distress and not postpartum depression, mood, or blues. Perinatal psychiatric distress and full-blown psychiatric disorders can emerge during either period, pregnancy or postpartum and relative to a myriad of biochemical and psychosocial factors. Limiting the discussion and nomenclature to ‘postpartum’ ignores women who are affected negatively by the pregnancy hormones and whose symptoms arise prior to delivery of the child.

Similarly, the hormone syndromes are not specifically depressive. Some of the hormones affected by childbirth are clearly anxiogenic (elicit anxiety) and by the nature of where their receptors are located, other hormones can affect memory, decision-making, impulse control, sensory perception and a wide variety of emotions, physiological and cognitive functions. By categorizing and limiting the syndrome to ‘depression’ even an atypical depression, as it is often referred to, fails to recognize the spectrum or severity of symptoms experienced.

Finally, for the same reasons I don’t use the phrase postpartum depression, I don’t ascribe to the characterization of the baby blues. When one thinks of the baby blues, one immediately thinks of a milder form of depression or sadness. Though useful as a popular term, it does nothing to distinguish what, in some cases, may be emotional expressions of the hormone-based, physiological changes occurring postpartum (or during pregnancy – though not often measured) and in other cases early markers for distress. Neither the term nor the scale used to assess the ‘condition’ has any predictive ability and fails to recognize a whole host of symptoms linked to perinatal hormone changes, that cause significant distress for the mom.

Because there are a myriad of hormones involved in carrying a pregnancy to term that are involved in number of physiological systems, and the symptom expression from those interactions is broad, limiting the focus to depressive type symptoms, unnecessarily limits the spectrum and severity of distress that some women experience. As with everything, if we don’t measure, we cannot manage. Part of measuring is figuring out what to measure. Depressive symptoms are certainly important, but they do not represent the totality of the symptoms experienced and so, we must expand the symptom base and re-work the diagnostic nomenclature.

Just Get to the Damned Research, Already!

Why have I spent so much time explaining the nature of postpartum research in general and my assumptions and perspectives specifically? Why haven’t I just told you what I learned? Well, because where you start determines where you end up, especially in science. Yes, I could have assumed the definitions and the research supporting those definitions of ‘postpartum depression’ were correct and then designed studies to support the appropriate hypotheses. It certainly would have been easier, but I didn’t. There were too many missing pieces and unanswered questions – things that just didn’t fit or make sense for me to go down that route. I had to create a new path – to throw everything in and let the pieces fall where they may. I had to let the data tell the story. I did and I will, let the data tell story.

Part two: Beyond Depression, Understanding Perinatal Mental Health.