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Depression and Its Effect on the Menstrual Cycle: A Comprehensive Review, Thesis of Medical Sciences

Uttarakhand Ayurved UniversityMedical Sciences

This research paper explores the complex relationship between depression and the menstrual cycle, examining the bidirectional influence of these factors on each other. It delves into the prevalence of depression in women, highlighting the gender disparity and the impact of hormonal fluctuations on mood disorders. The paper investigates the association between depression and various menstrual abnormalities, including dysmenorrhea, menorrhagia, and premenstrual syndrome, providing insights into the underlying mechanisms and potential treatment strategies. It also discusses the implications of depression on the timing of menopause and the potential for early perimenopause and menopause in women with depression. The paper concludes by emphasizing the need for further research to understand the intricate interplay between depression and the menstrual cycle, ultimately aiming to improve the well-being of women.

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As a library, NLM provides access to scientific literature. Inclusion in an NLM database does
not imply endorsement of, or agreement with, the contents by NLM or the National Institutes
of Health.
Learn more: PMC Disclaimer | PMC Copyright Notice
Cureus. 2021 Jul 21;13(7):e16532. doi: 10.7759/cureus.16532
Depression and Its Eect on the Menstrual Cycle
Jaskamal Padda 1,2,✉, Khizer Khalid 1, Gazala Hitawala 1, Nitya Batra 1, Sindhu Pokhriyal 1, Ayushi Mohan
1, Ujala Zubair 3, Ayden Charlene Cooper 1, Gutteridge Jean-Charles 1,4
Editors: Alexander Muacevic, John R Adler
Author information Article notes Copyright and License information
PMCID: PMC8378322 PMID: 34430141
Abstract
A strong association is noted between depression and early perimenopause as well as menopause. The
association was found to be the greatest in women with natural menopause at theage less than 40
years. Excessive corticotropin-releasing hormone (CRH) levels in depression lead to inhibition of the
hypothalamic-pituitary-gonadal (HPG) axis and increased cortisol levels which further inhibits the
action of gonadotropin-releasing hormone (GnRH) neurons, gonadotrophs, and gonads. The resulting
changes in luteinizing hormone (LH) amplitude, follicle-stimulating hormone (FSH) levels, and LH pulse
frequency were noted in patients with depression.
Besides depression, earlier surgical menopause is associated with cognitive decline. In addition, it is
seen that menopausal changes predisposed females to an increased risk of depression. The association
between dysmenorrhea and depression was found to be bidirectional and congruent in most studies.
Patients with dysmenorrhea and coexisting depressionhad enhanced pain perception along with a
poor response to pain relief measures. Even the treatment of underlying depression has been shown to
cause menorrhagia. On the other hand, amenorrhea has also been reported as a side effect of sertraline
and electroconvulsive therapy. Menstrual disorders contribute to a significant number of outpatient
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Download Depression and Its Effect on the Menstrual Cycle: A Comprehensive Review and more Thesis Medical Sciences in PDF only on Docsity!

As a library, NLM provides access to scientific literature. Inclusion in an NLM database does

not imply endorsement of, or agreement with, the contents by NLM or the National Institutes

of Health.

Learn more: PMC Disclaimer | PMC Copyright Notice

Cureus. 2021 Jul 21;13(7):e16532. doi: 10.7759/cureus.

Depression and Its Eect on the Menstrual Cycle

Jaskamal Padda 1,2,✉, Khizer Khalid 1 , Gazala Hitawala 1 , Nitya Batra 1 , Sindhu Pokhriyal 1 , Ayushi Mohan

1 , Ujala Zubair 3 , Ayden Charlene Cooper 1 , Gutteridge Jean-Charles 1,

Editors: Alexander Muacevic, John R Adler

Author information Article notes Copyright and License information

PMCID: PMC8378322 PMID: 34430141

Abstract

A strong association is noted between depression and early perimenopause as well as menopause. The association was found to be the greatest in women with natural menopause at the age less than 40 years. Excessive corticotropin-releasing hormone (CRH) levels in depression lead to inhibition of the hypothalamic-pituitary-gonadal (HPG) axis and increased cortisol levels which further inhibits the action of gonadotropin-releasing hormone (GnRH) neurons, gonadotrophs, and gonads. The resulting changes in luteinizing hormone (LH) amplitude, follicle-stimulating hormone (FSH) levels, and LH pulse frequency were noted in patients with depression.

Besides depression, earlier surgical menopause is associated with cognitive decline. In addition, it is seen that menopausal changes predisposed females to an increased risk of depression. The association between dysmenorrhea and depression was found to be bidirectional and congruent in most studies. Patients with dysmenorrhea and coexisting depression had enhanced pain perception along with a poor response to pain relief measures. Even the treatment of underlying depression has been shown to cause menorrhagia. On the other hand, amenorrhea has also been reported as a side effect of sertraline and electroconvulsive therapy. Menstrual disorders contribute to a significant number of outpatient

gynecological visits per year in the United States. Co-existing or history of depression can either be the cause of or interfere in the treatment of these disorders. Furthermore, the treatment of depression can be the etiology of various menstrual abnormalities, while menstrual disorders themselves could be the cause of depression. The increasing prevalence of depression, women’s health, multiple female-specific subtypes, and the preexisting burden of menstrual disorders necessitates more detailed studies on the effects of depression on the menstrual cycle.

Keywords: depression, menstrual cycle, menorrhagia, dysmenorrhea, antidepressants

Introduction and background

Major depressive disorder (MDD) is associated with significant gender disparity. Women are afflicted with depression twice more likely than men, and it is the second leading cause of disease burden for women in the United States [ 1 , 2 ]. The lifetime prevalence of MDD is 26.1% among women whereas it is 14.7% among men in the United States [ 3 ]. Moreover, depressive disorders such as premenopausal dysphoric disorder and postpartum depression are gender-specific. Interaction between various factors namely neurobiological, hormonal, genetic, social, environmental has been implicated to explain these differences [ 4 - 6 ]. Structural differences between the brains of men and women, altered sensitivity to various neurotransmitters and hormones like serotonin, gamma-aminobutyric acid (GABA), allopregnanolone, estrogen, and corticosteroids along with genetic predisposition and cultural factors, such as lower health-seeking behaviors, social isolation, high incidence of abuse, and marital and child- rearing stressors, contribute to the development of depression in women [ 4 - 6 ]. This increased susceptibility is seen only during reproductive years, especially during premenstrual, pregnancy, and perimenopausal phase. The prevalence of depression in prepuberty and after the age of 55 years is almost equal between males and females [ 4 ].

Women diagnosed with MDD are more likely to experience severe disease with somatic symptoms and a higher degree of functional impairment [ 7 - 9 ]. One of such under-recognized yet very pertinent symptoms is menstrual cycle abnormalities, including dysmenorrhea, menorrhagia, menstrual irregularities, and premenstrual symptoms [ 10 - 12 ]. A study in 2012 concluded that there is an increased incidence of heavy menstrual bleeding by 1.89 times in women with a past medical history of MDD [ 10 ]. The more symptoms that a woman presents with heavy bleeding, gushing, passage of clots, the stronger the association with a history of MDD. This can be due to higher variability in hormonal levels or because of over-awareness and higher reporting of distressing symptoms [ 10 ]. Other than menstruation disorders, MDD is a risk factor for several other disorders as well, such as cardiovascular disease, diabetes, dizziness, and chronic pain. The plausible reasons for this are unhealthy lifestyles in depressed patients like smoking, alcohol, drug use, physical inactivity, sleep disturbances, non- compliance with medical regimens in addition to varied sensory perception and dysregulation of autonomic, inflammatory, and immune systems [ 13 , 14 ].

Table 1. Symptoms of Major Depressive Disorder.

Symptoms Low mood Anhedonia Unintentional weight changes Change in sleep duration Excessive tiredness Psychomotor retardation Feeling blameworthy or valueless Finding it difficult to focus and take decisions Suicidal ideations

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Depression and its effect on hormones

There are multiple reports that establish the influence of reproductive hormones on depression [ 16 - 18 ]. Conversely, depression also plays a role in the regulation of reproductive hormones. The hypothalamic- pituitary-adrenal (HPA) axis is activated during stress, which results in the secretion of CRH from the hypothalamus. CRH acts on the pituitary, facilitating the release of adrenocorticotropic hormone (ACTH), which interacts with the adrenal cortex and stimulates the release of cortisol. In MDD, chronic stress results in a dysregulated HPA axis [ 19 , 20 ]. It is evident that stress-induced glucocorticoids inhibit the action of gonadotropin-releasing hormone (GnRH) neurons, gonadotrophs, and the gonads (Figure 1 ) [ 21 ]. Additionally, excessive CRH levels in depression lead to inhibition of the hypothalamic- pituitary-gonadal (HPG) axis [ 22 - 24 ].

Figure 1. Depression Aecting Reproductive Hormones.

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Image created by the author Gazala Hitawala.

The existing literature depicts a variable impact of depression on the gonadotropin hormones. Depression has a variant effect discreetly on the follicle-stimulating hormone (FSH) levels, mean luteinizing hormone (LH) levels, the LH pulsatility, and the estrogen levels. A study in 1997 reported

Depression and its association with earlier menopause

It is acclaimed that menopause is marked by an array of hormonal fluctuations, decline in ovarian function, sleep disturbances, and vasomotor symptoms [ 38 , 39 ]. The aforementioned menopausal attributes are preceded by perimenopause. Perimenopause is the time during which the body undergoes physiological changes to progress to menopause [ 40 ]. It is pertinent that these menopausal changes in women's life are associated with mood symptoms [ 16 , 41 ]. As discussed ahead, it is established that depression affects the reproductive hormone regulation in females [ 25 , 26 , 29 ]. Thus, it is significant to explore the association between depression and menopause.

The Harvard study of moods and cycles observed that women without a history of depression were at an increased risk of depressive symptoms when entering perimenopause compared to premenopausal women [ 42 ]. It was also evident in another study that females were at an increased risk of depressive symptoms and MDD when entering perimenopause [ 43 ]. Laterally, in a study following 332 depressed women and 644 non-depressed women over 36 months, it was observed that women with depression experienced early perimenopause. Moreover, there was also a correlation between the severity of depression and progression to perimenopause. Women with severe depression (Hamilton Rating Scale for Depression scores >8) had a two times faster rate of entering perimenopause compared to the non- depressed women [ 44 ].

A similar pattern was also reported of early menopause in females with a history of depression. A study reported that 14% of females with early menopause had a history of medically treated depression for at least one year, compared to 6% control (premenopausal female or naturally menopausal after 47 years of age). The association with depression was greatest in women with natural menopause at an age less than 40 years. Moreover, there were four times increased risk of early menopause with greater than three years of depression treatment [ 45 ]. A study in Canada on 13,216 women aged 45-64 years reported that women who self-reported increased depression on the Center for Epidemiologic Studies Short Depression Scale-10 (CESD-10) had experienced premature menopause with the odds ratio of 1.45 (95% CI 1.07-1.97) [ 46 ]. Parallel to the mentioned reports, in a meta-analysis, women with premature menopause (age < 40 years) had a two-fold increased risk of depression compared to their counterparts who had menopause at age ≥ 40 years [ 47 ]. In addition to it, earlier surgical menopause (hysterectomy or unilateral or bilateral oophorectomy) was also associated with cognitive decline. It was reported that women with an early age at surgical menopause had a relatively rapid decline in global cognitive function compared to older women at the time of surgical menopause. Besides, each year of earlier surgical menopause was homologous to the effect associated with six months of aging. Furthermore, a similar association was also seen with the lesser duration of the reproductive period (the period between menarche and menopause) [ 48 ]. Thus, it is explicit that there is a strong association between depression and early perimenopause together with early menopause.

Depression and its association with menorrhagia

Menorrhagia is a predominant complaint in women of the reproductive age group with an annual prevalence rate of 53 per 1000 women, contributing to 20-30% outpatient gynecological visits per year in the United States [ 49 ]. About 45% of hysterectomies are performed for the treatment of menorrhagia [ 50 ]. It is a consensus that menorrhagia is caused by gynecological pathology, but it can also be a presentation of depression. Though menorrhagia and other forms of gynecological morbidities can precipitate depression, there are few studies indicating that history of depression may precede heavy menstrual bleeding [ 10 , 12 , 51 - 53 ]. It has been well established that stress can lead to menstrual cycle changes by altering HPG and HPA axis [ 54 , 55 ].

In 2012, a study conducted on women aged 42-52 years demonstrated that 67.7% of women reported heavy bleeding. The rate of past and recent major depression was significantly higher among these women, 39% and 14%, whereas it was lower for women reporting no menorrhagia, 24% and 8%. A dose-effect relation was also established, with a stronger association between past depression and a number of menorrhagia symptoms reported (heavy bleeding, flooding/gushing, and passage of clots) [ 10 ]. Another study done on 126 North Korean women in South Korea showed that the prevalence of depression was 40%, and of that, menorrhagia was 19.8%. It also revealed that depression and the number of menstrual complaints were significantly correlated. This was explained by higher levels of blood bradykinin and prostaglandin associated with stress, which causes dilatation and increase in flow in pelvic blood vessels and hence causing menorrhagia and pelvic pain [ 12 ]. One study which analyzed the data from the 2002 national Health Interview Survey determined that 19% of women experienced menstrual problems including menorrhagia, dysmenorrhea, and premenstrual syndrome and they are twice more likely to suffer from depression and anxiety than those without menstrual complaints. Additionally, they are 1.7 to three times more likely to report sadness, hopelessness, insomnia, and nervousness [ 51 ]. Segregation into cases vs non-cases was based on a 60-item general health questionnaire [ 53 ].

Depression can not only precede but can also hinder the treatment for menorrhagia. A study from 2007 reported that mild depression, six months from baseline, was associated with discontinuation of levonorgestrel-releasing intrauterine system treatment, effective treatment of menorrhagia, and led to higher hysterectomy rates in this group [ 56 ]. Even the treatment of underlying depression can cause menorrhagia. A case report from 2010 described an adolescent girl with MDD who developed menorrhagia three weeks after treatment with sertraline [ 57 ]. Another case report from 1992 illustrated a 40-year-old woman who developed heavy menstrual bleeding one month after commencing fluoxetine and spontaneous ecchymoses in two months [ 58 ]. Her symptoms subsided four days after stopping the medication. Amenorrhea has also been reported as a side effect of sertraline and electroconvulsive therapy [ 59 , 60 ].

Depression and its association with dysmenorrhea

the severity of dysmenorrhea. Second, they found a link between history of treated depression and the severity of menstrual problems [ 72 , 73 ].

These studies are in line with those by Pedron-Neuvo et al. and many others in which depression has been found to have a strong association with menstrual pain. However, more studies are needed to establish the mechanism by which depression causes dysmenorrhea [ 74 ].

In addition, interpreting pain objectively is a challenge in itself, as a woman's observation of pain may differ based on their personalities, social circumstances, life experiences, and several other occult influences. Although sophisticated imaging techniques such as functional magnetic resonance imaging (fMRI) have made it possible to map regions in the brain associated with painful conditions such as dysmenorrhea, these areas need more studies to help us get a better understanding of the subject [ 75 ].

Depression and its association with premenstrual syndrome

Right before women get their periods, they may experience a range of symptoms which are classified as premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD) depending on whether they are mild or severe. PMS includes symptoms like bloating, mood swings, feeling sad or hopeless, inability to concentrate, breast soreness, fatigue, and headaches. When these symptoms become so severe that they interfere with day-to-day functioning, they are called PMDD [ 76 ]. Various studies have cited the incidence of clinically significant PMS to be up to 8% and PMDD to be around 2% [ 77 , 78 ].

Several studies on neuropsychobiology like that by Taylor et al. and Rapkin et al. have shown that patients with PMS and PMDD have lower circulating levels of serotonin [ 79 , 80 ]. This has been hypothesized to be secondary to the cyclic hormone changes that occur during the luteal phase of menstrual cycle owing to the altered neurotransmitter production following these cyclical hormone changes [ 81 ].

It is well-known that depression is also associated with decreased circulating serotonin levels and the use of selective serotonin reuptake inhibitors (SSRI) in the treatment of depression has been an established way of treating both depression and PMDD [ 82 ]. The American Psychiatric Association has included PMDD as one of the subtypes of depression [ 83 ]. The notable clinical feature that separates the two clinical entities is the typical association of the depressive symptoms of PMDD with the luteal phase of the menstrual cycle [ 76 ].

Effect of antidepressants and ECT on menstrual cycle

Antidepressant medications are a broad and expansile group of medications that include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine

oxidase (MAO) inhibitors. Several herbal supplements like St. John’s Wort are also commonly used over the counter to combat depressive symptoms. The relationship between menstrual abnormalities and antidepressants is a relatively less common phenomenon and continues to surprise physicians in daily practice [ 58 ].

A multicentric, cross-sectional study conducted by Uguz et al. analyzed 793 women on antidepressants and 639 women not on any medications. They reported that menstrual disorders were more common in women taking antidepressants with an incidence of 14.5% and the most implicated antidepressants belonged to the SSRI and SNRI subgroups. Mirtazapine was also implicated especially when it was used in combination with SSRIs and SNRIs [ 84 ].

Paradoxically, while SSRIs are the first-line drugs of choice used by many practitioners for the treatment of PMS-like symptoms, they can also rarely cause menstrual irregularities like amenorrhea. Albeit rare, the endocrine and reproductive adverse effects of SSRIs have been reported in several studies [ 85 , 86 ].

Kim and Park conducted a cross-sectional pilot study, in which they measured prolactin levels in all patients who had received SSRI monotherapy for a mean of 14.75 months. They concluded that although SSRI therapy can induce hyperprolactinemia, there was no correlation between the dosage of SSRIs nor did the prevalence of hyperprolactinemia vary amidst different SSRIs [ 87 ]. Although very rare, there have been case reports of SSRIs affecting thyroid function which are well-known to be associated with menstrual irregularities [ 88 ]. Similar to SSRIs, duloxetine, which is an SNRI commonly used to treat depression when it occurs in combination with conditions like diabetic neuropathy and fibromyalgia has also been associated with hyperprolactinemia and amenorrhea [ 89 ]. The mechanisms suggested in SSRI- and SNRI-induced hyperprolactinemia are by direct inhibition of the tuberoinfundibular pathway, as well as by possible direct stimulation of postsynaptic serotonergic receptors [ 58 ].

Another frequently used herb for treating depression is St John’s Wort (SJW) which is a well-known inducer of cytochrome P450 3A4 9(CYP3A4) and hence known for its interactions with several drugs including oral contraceptive pills (OCPs) and warfarin. SJW, by increasing the activity of CYP3A4, reduces the plasma levels of estrogen causing withdrawal bleeding of the endometrium. Breakthrough menstrual bleeding is therefore a frequently encountered side effect of this herb when used alongside OCPs [ 90 ]. SJW also interacts with SSRIs in the very same way as many serotonergic drugs like tramadol. It is known to increase the serotonin levels in the brain and can cause moderate serotonin syndrome in patients taking both SSRIs and SJW concurrently [ 91 ].

Finally, another frequently forgotten adverse effect is that of electroconvulsive therapy (ECT) causing amenorrhea. ECT is a safe and effective modality for managing mental health conditions like major

The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.

Footnotes

The authors have declared that no competing interests exist.

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