Open Access Review

Article DOI: 10.7759/cureus.16532

Depression and Its Effect 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

1. Internal Medicine, JC Medical Center, Orlando, USA 2. Internal Medicine, Avalon University School of Medicine,
Willemstad, CUW 3. Family Medicine, Dow University of Health Sciences, Karachi, PAK 4. Internal Medicine, Advent
Health and Orlando Health Hospital, Orlando, USA

Corresponding author: Jaskamal Padda, [email protected]

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.

Categories: Internal Medicine, Obstetrics/Gynecology, Psychology

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
Review began 06/27/2021 the United States [1,2]. The lifetime prevalence of MDD is 26.1% among women whereas it is 14.7% among
Review ended 07/06/2021
men in the United States [3]. Moreover, depressive disorders such as premenopausal dysphoric disorder and
Published 07/21/2021
postpartum depression are gender-specific. Interaction between various factors namely neurobiological,
© Copyright 2021 hormonal, genetic, social, environmental has been implicated to explain these differences [4-6]. Structural
Padda et al. This is an open access article
differences between the brains of men and women, altered sensitivity to various neurotransmitters and
distributed under the terms of the
Creative Commons Attribution License hormones like serotonin, gamma-aminobutyric acid (GABA), allopregnanolone, estrogen, and
CC-BY 4.0., which permits unrestricted corticosteroids along with genetic predisposition and cultural factors, such as lower health-seeking
use, distribution, and reproduction in any behaviors, social isolation, high incidence of abuse, and marital and child-rearing stressors, contribute to
medium, provided the original author and
the development of depression in women [4-6]. This increased susceptibility is seen only during
source are credited.
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].

How to cite this article

Padda J, Khalid K, Hitawala G, et al. (July 21, 2021) Depression and Its Effect on the Menstrual Cycle. Cureus 13(7): e16532. DOI
10.7759/cureus.16532
 The burden of menstrual abnormalities caused by MDD should not be underestimated. Primary care
physicians and gynecologists treating women with menstrual disorders should follow a multidisciplinary
approach including a depression screening. Patients should be made aware of the common symptoms of
depression, comorbidities, coping mechanisms, and treatment options. Close follow-up should be ensured
for early detection and intervention. Moreover, the literature available on the effects of depression on the
menstrual cycle is limited and most of them are over a decade old. The temporal relationship between
depression and menstruation is not clearly elucidated in present studies. Given the load of depression and
menstrual disorders in women, new research using the latest diagnostic criteria for depression is
necessary [10].

Review
Defining major depressive disorder
Major depressive disorder (MDD) is a disease that affects our mood, thought processes, and actions.
Depression includes a spectrum of symptoms that categorizes the patient from mild to severe. Minimum
duration of two weeks of symptoms with a decline in functioning is required for diagnosing depression. In
addition, general medical conditions like thyroid disorders must be ruled out since they can present in a
similar way. MDD can present with many symptoms (Table 1) [15].

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

TABLE 1: Symptoms of Major Depressive Disorder

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].

2021 Padda et al. Cureus 13(7): e16532. DOI 10.7759/cureus.16532 2 of 10

 FIGURE 1: Depression Affecting Reproductive Hormones
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 that depressed women had
higher LH amplitudes. However, there was no significant difference in the number of LH pulses over an
eight-hour period [25]. In the year 2000, Young et al. conducted a similar study on reproductive-age women
with major depressive disorder. There was no difference in the FSH levels, LH pulse frequency, and LH
amplitude compared to the controls [26]. Furthermore, the reanalysis of the studies in 2003 resolved the
discrepancy by confirming that LH pulsatility was decreased in the follicular phase of the menstrual cycle
within depressed women of childbearing age [27]. It is evident that LH pulsatility plays a role in the
regulation of the menstrual cycle. It avoids down-regulation of the GnRH receptors in the pituitary, which is
crucial to maintain a normal hypothalamic-gonadal feedback loop. Furthermore, LH pulsatility determines
ovulation. Thus, decreased LH pulsatility in depressed women can cause menstrual irregularities and can
also affect fertility [28]. Correspondingly, a study on postmenopausal women with primary affective disorder
reported decreased LH levels in the depressive phase. Moreover, decreased LH levels were also observed
during the normothymic phase of the disease, suggesting that the findings were irrespective of the
symptoms [29]. Another study on postmenopausal women reported 33% reduced LH concentration in
postmenopausal depressed women compared to their normal counterparts. Additionally, 50% of the
depressed women had LH levels lower than the lowest control value [30]. It is hypothesized that the HPG axis
is disrupted in menopausal women with depression, ranging from hyperactivity in the perimenopausal
period and gradually regressing to subnormal function after menopause [31].

Contrary to the effect of depression on the LH levels, the FSH levels were not significantly affected [26,32].
Studies in menopausal and perimenopausal women have reported no significant difference in the baseline
FSH levels of the depressed participants [33,34]. Subsequently, in a 2003 study on women attending
menopausal clinics, between the ages of 40 years and 55 years with depression, there was an observed
association between the declining FSH levels and the declining Center for Epidemiologic Studies Depression
(CES-D) scale scores over a six-week period. There was a proportionate association between the CES-D score
and the FSH levels. In a nutshell, women with high CES-D score had high FSH levels, and vice-
versa. However, with a repeated cross-sectional study, the depressed women could not be differentiated from

2021 Padda et al. Cureus 13(7): e16532. DOI 10.7759/cureus.16532 3 of 10

 the non-depressed women based on their FSH levels [35].

The mean estradiol levels are lower in the follicular phase of the menstrual cycle in women with
depression [26,36]. Furthermore, a study demonstrated the effect of 17b-estradiol on the stress circuit of the
brain, including the amygdala, hippocampus, and hypothalamus; it was found that during the low estradiol
phase of the menstrual cycle (early follicular phase) there was robust activity in the stress circuit compared
to the high estradiol phase (late follicular/ midcycle phase) in healthy individuals. However, this difference
was not observed in the depressed patients, indicating that in depressed patients the estradiol capacity to
evoke neuronal response was absent [37]. As stated above, it is also hypothesized that the lower estradiol
levels can either be due to gonadal dysfunction or decreased LH pulse in depression [26].

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

2021 Padda et al. Cureus 13(7): e16532. DOI 10.7759/cureus.16532 4 of 10

 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

Dysmenorrhea, which is the most common menstrual disorder seen in reproductive women, can be primary
or secondary based on its etiology. Primary dysmenorrhea is classified as painful menstrual cramps without
any pelvic pathology and is the more common variant, while secondary dysmenorrhea is associated with
pelvic pathologies such as endometriosis, fibroid uterus, etc. [61,62]. There is considerable overlap in the
definitions of dysmenorrhea and premenstrual syndrome (PMS). PMS-like syndrome refers to the presence of
at least one mood symptom (anxiety, mood lability, irritability, marked anger, dysthymia) and/or physical
symptom (abdominal cramps, back pain, joint pains, mastalgia, headaches, weight gain, feeling
bloated) [63]. Three percent to 33% of women suffering from dysmenorrhea and up to 8% of women with
PMS face issues with normal functionality of their everyday life [64,65]. The present systematic review has
been designed to focus on the association between dysmenorrhea and depression.

The association between dysmenorrhea and depression was found to be bidirectional and congruent in most
studies. Rodrigues et al. conducted a study of 274 adolescents and young adults with menstrual
abnormalities. It mentioned depression as the most common limitation affecting the quality of life of these
young women (42.5%), whereas other studies described how the simultaneous presence of depression and
dysmenorrhea pointed towards enhanced pain perception along with poor response to pain relief measures
in this patient population [66].

Pain and depression have had a well-known association. American psychologist, Mark Jensen, has discussed
the strong association of depression and idiopathic pain disorders and described the successful use of
cognitive as well as behavior therapies in treating pain [67]. Jarvik et al. in their study reported depression to
be the strongest predictor of incident back pain compared to any other clinical or anatomical predictors [68].

Not surprisingly, painful menses or dysmenorrhea also seems to have a convincing association with
depression. Lacovides et al. in his critical review in 2015 proposed an alternative hypothesis for increased
pain sensitivity in severe dysmenorrhea. They suggested that an increased level of prostaglandins triggering
uterine muscle contractions alone cannot explain the pain in dysmenorrhea. They went on to say that
increased central sensitivity to pain is probably what leads to enhanced peripheral response to pain in
patients with severe dysmenorrhea [69]. Balik et al. in their study on 159 adolescent girls found the
prevalence of dysmenorrhea to be 67.9% and described the Beck Depression score (BDS) in these patients to
be averaging at 19.1+/-11.85 [70]. A Turkish study conducted by Unsal et al. also reported a positive
correlation between the severity of dysmenorrhea and mean BDS (p < 0.05). They also reported a higher
prevalence of depression in females experiencing dysmenorrhea compared to those who didn’t have
dysmenorrhea [71].

In another relevant study on women attending the gynecological clinic for menstrual problems such as PMS,
menorrhagia, and dysmenorrhea, there were two important conclusions drawn. The first was in sync with
several previous studies and stated that severity of depression was directly proportional to 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

2021 Padda et al. Cureus 13(7): e16532. DOI 10.7759/cureus.16532 5 of 10

 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
depression and bipolar disorder which have not responded to medications and psychotherapy. ECT is rarely
used to treat these refractory mental health conditions but remains a viable option in mental health
treatment. Michael, who studied 687 female in-patients undergoing ECT, reported that the most frequent
pattern seen during ECT was amenorrhea followed by a shortening of the first cycle, with a following longer
cycle of more than 30 days. He also reported a remarkable increase in the length of the menstrual cycle in
women who received between 10-20 shock treatments [92,93]. Thankfully these adverse effects are transient

2021 Padda et al. Cureus 13(7): e16532. DOI 10.7759/cureus.16532 6 of 10

 and benign. The exact mechanism of this is still unknown but several studies have pointed towards robust
but transient hyperprolactinemia that occurs during therapy [92,93].

Conclusions
In this study, we can conclude that depression and the menstrual cycle are interconnected, and
abnormalities in either of them can affect the other. Hormonal changes in the body during menopause
predispose them to depression. Depression alters the hypothalamic-pituitary axis which leads to menstrual
irregularities. Our results demonstrate that women with depressive disorders have a faster rate of
progression to menopause. Menorrhagia and depression are also linked to each other, with depressed
patients experiencing more severe symptoms. Depression increases sensitivity to pain-causing
dysmenorrhea and thus hinders the management of menorrhagia and dysmenorrhea. Further studies should
be conducted to identify the mechanism by which depression causes dysmenorrhea.

Women undergoing disturbances in the menstrual cycle should be screened for depression and similarly,
women experiencing depressive disorders should be evaluated for irregularities in menstruation.
Antidepressants have not been proven to be helpful in these patients. Stabilizing the menstrual cycle and
providing psychological support using behavioral therapy and coping strategies can help improve the quality
of life of these patients. Further research is required in this modality to explain the pathways
interconnecting depression and the menstrual cycle in order to come up with treatment strategies in helping
women.

MDD-induced menstrual abnormalities should not be overlooked. A multidisciplinary approach, including

screening to rule out MDD, should be applied by the primary care physician and gynecologist when treating
women with menstrual disorders. Such patients should also be educated on common symptoms of
depression, comorbidities, coping mechanisms, and treatment options. Close follow-up should be provided
for immediate diagnosis and treatment. Treatment for underlying depression has been affiliated with
menorrhagia, while amenorrhea has been reported with sertraline and electroconvulsive therapy. Further
investigations should also be conducted on discovering an effective way to treat depression in women
without causing menstrual abnormalities.

Additional Information
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the
following: Payment/services info: All authors have declared that no financial support was received from
any organization for the submitted work. Financial relationships: All authors have declared that they have
no financial relationships at present or within the previous three years with any organizations that might
have an interest in the submitted work. Other relationships: All authors have declared that there are no
other relationships or activities that could appear to have influenced the submitted work.

References
1. Alexander JL: Quest for timely detection and treatment of women with depression . J Manag Care Pharm.
2007, 13:3-11. 10.18553/jmcp.2007.13.9-a.3
2. Peden AR: Up from depression: strategies used by women recovering from depression . J Psychiatr Ment
Health Nurs. 1994, 1:77-83. 10.1111/j.1365-2850.1994.tb00023.x
3. Hasin DS, Sarvet AL, Meyers JL, Saha TD, Ruan WJ, Stohl M, Grant BF: Epidemiology of adult DSM-5 major
depressive disorder and its specifiers in the United States. JAMA Psychiatry. 2018, 75:336-46.
10.1001/jamapsychiatry.2017.4602
4. Harris T: Depression in women and its sequelae . J Psychosom Res. 2003, 54:103-12. 10.1016/s0022-
3999(02)00500-7
5. Rubinow DR, Schmidt PJ, Roca CA: Hormonal and gender influences on mood regulation .
Neuropsychopharmacology: The 5th Generation of Progress. Davis KL, Charney D, Coyle JT, Nemeroff C
(ed): Lippincott Williams & Wilkins, Philadelphia, PA; 2002. 1165-78.
6. Burt VK, Stein K: Epidemiology of depression throughout the female life cycle . J Clin Psychiatry. 2002, 63:9-
15.
7. Ensom MH: Gender-based differences and menstrual cycle-related changes in specific diseases: implications
for pharmacotherapy. Pharmacotherapy. 2000, 20:523-39. 10.1592/phco.20.6.523.35161
8. Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB: Sex and depression in the national comorbidity
survey I: lifetime prevalence, chronicity and recurrence. J Affect Disord. 1993, 29:85-96. 10.1016/0165-
0327(93)90026-g
9. Kornstein SG: Gender differences in depression: implications for treatment . J Clin Psychiatry. 1997, 58:12-
18.
10. Bromberger JT, Schott LL, Matthews KA, et al.: Association of past and recent major depression and
menstrual characteristics in midlife: study of Women's Health Across the Nation. Menopause. 2012, 19:959-
66. 10.1097/gme.0b013e318248f2d5
11. Kayhan F, Alptekin H, Kayhan A: Mood and anxiety disorders in patients with abnormal uterine bleeding .
Eur J Obstet Gynecol Reprod Biol. 2016, 199:192-7. 10.1016/j.ejogrb.2016.02.033
12. Kim HK, Kim HS, Kim SJ: Association of anxiety, depression, and somatization with menstrual problems
among North Korean women defectors in South Korea. Psychiatry Investig. 2017, 14:727-33.

2021 Padda et al. Cureus 13(7): e16532. DOI 10.7759/cureus.16532 7 of 10

 13. Hotopf M, Mayou R, Wadsworth M, Wessely S: Temporal relationships between physical symptoms and
psychiatric disorder. Results from a national birth cohort. Br J Psychiatry. 1998, 173:255-61.
10.1192/bjp.173.3.255
14. Rozanski A, Blumenthal JA, Kaplan J: Impact of psychological factors on the pathogenesis of cardiovascular
disease and implications for therapy. Circulation. 1999, 99:2192-217. 10.1161/01.cir.99.16.2192
15. What is depression?. (2020). Accessed: June 8, 2021: https://www.psychiatry.org/patients-
families/depression/what-is-depression.
16. Soares CN, Zitek B: Reproductive hormone sensitivity and risk for depression across the female life cycle: a
continuum of vulnerability?. J Psychiatry Neurosci. 2008, 33:331-43.
17. Slavich GM, Sacher J: Stress, sex hormones, inflammation, and major depressive disorder: extending social
signal transduction theory of depression to account for sex differences in mood disorders.
Psychopharmacology (Berl). 2019, 236:3063-79. 10.1007/s00213-019-05326-9
18. Smeeth DM, Dima D, Jones L, et al.: Polygenic risk for circulating reproductive hormone levels and their
influence on hippocampal volume and depression susceptibility. Psychoneuroendocrinology. 2019, 106:284-
92. 10.1016/j.psyneuen.2019.04.011
19. Varghese FP, Brown ES: The hypothalamic-pituitary-adrenal axis in major depressive disorder: a brief
primer for primary care physicians. Prim Care Companion J Clin Psychiatry. 2001, 3:151-5.
20. Keller J, Gomez R, Williams G, Lembke A, Lazzeroni L, Murphy GM Jr, Schatzberg AF: HPA axis in major
depression: cortisol, clinical symptomatology and genetic variation predict cognition. Mol Psychiatry. 2017,
22:527-36. 10.1038/mp.2016.120
21. Joseph DN, Whirledge S: Stress and the HPA axis: balancing homeostasis and fertility . Int J Mol Sci. 2017,
18:2224. 10.3390/ijms18102224
22. Claes SJ: Corticotropin-releasing hormone (CRH) in psychiatry: from stress to psychopathology . Ann Med.
2004, 36:50-61. 10.1080/07853890310017044
23. Claes SJ: CRH, stress, and major depression: a psychobiological interplay . Vitam Horm. 2004, 69:117-50.
10.1016/S0083-6729(04)69005-4
24. Raftogianni A, Roth LC, García-González D, et al.: Deciphering the contributions of CRH receptors in the
brain and pituitary to stress-induced inhibition of the reproductive axis. Front Mol Neurosci. 2018, 11:305.
10.3389/fnmol.2018.00305
25. Meller WH, Zander KM, Crosby RD, Tagatz GE: Luteinizing hormone pulse characteristics in depressed
women. Am J Psychiatry. 1997, 154:1454-5. 10.1176/ajp.154.10.1454
26. Young EA, Midgley AR, Carlson NE, Brown MB: Alteration in the hypothalamic-pituitary-ovarian axis in
depressed women. Arch Gen Psychiatry. 2000, 57:1157-62. 10.1001/archpsyc.57.12.1157
27. Grambsch P, Young EA, Meller WH: Pulsatile luteinizing hormone disruption in depression .
Psychoneuroendocrinology. 2004, 29:825-9. 10.1016/S0306-4530(03)00146-X
28. Tsutsumi R, Webster NJ: GnRH pulsatility, the pituitary response and reproductive dysfunction . Endocr J.
2009, 56:729-37. 10.1507/endocrj.k09e-185
29. Brambilla F, Maggioni M, Ferrari E, Scarone S, Catalano M: Tonic and dynamic gonadotropin secretion in
depressive and normothymic phases of affective disorders. Psychiatry Res. 1990, 32:229-39. 10.1016/0165-
1781(90)90028-4
30. Altman N, Sachar EJ, Gruen PH, Halpern JS, Eto S: Reduced plasma LH concentration in postmenopausal
depressed women. Psychosom Med. 1975, 37:274-6. 10.1097/00006842-197505000-00005
31. O'Toole SM, Rubin RT: Neuroendocrine aspects of primary endogenous depression--XIV. Gonadotropin
secretion in female patients and their matched controls. Psychoneuroendocrinology. 1995, 20:603-12.
10.1016/0306-4530(95)00006-a
32. Undén F, Ljunggren JG, Beck-Friis J, Kjellman BF, Wetterberg L: Hypothalamic-pituitary-gonadal axis in
major depressive disorders. Acta Psychiatr Scand. 1988, 78:138-46. 10.1111/j.1600-0447.1988.tb06313.x
33. Saletu B, Brandstätter N, Metka M, et al.: Hormonal, syndromal and EEG mapping studies in menopausal
syndrome patients with and without depression as compared with controls. Maturitas. 1996, 23:91-105.
10.1016/0378-5122(95)00946-9
34. Schmidt PJ, Murphy JH, Haq N, Danaceau MA, St Clair L: Basal plasma hormone levels in depressed
perimenopausal women. Psychoneuroendocrinology. 2002, 27:907-20. 10.1016/s0306-4530(02)00004-5
35. Daly RC, Danaceau MA, Rubinow DR, Schmidt PJ: Concordant restoration of ovarian function and mood in
perimenopausal depression. Am J Psychiatry. 2003, 160:1842-6. 10.1176/appi.ajp.160.10.1842
36. Young EA, Korszun A: The hypothalamic-pituitary-gonadal axis in mood disorders . Endocrinol Metab Clin
North Am. 2002, 31:63-78. 10.1016/s0889-8529(01)00002-0
37. Jacobs EG, Holsen LM, Lancaster K, et al.: 17β-estradiol differentially regulates stress circuitry activity in
healthy and depressed women. Neuropsychopharmacology. 2015, 40:566-76. 10.1038/npp.2014.203
38. Nelson HD: Menopause. Lancet. 2008, 371:760-70. 10.1016/S0140-6736(08)60346-3
39. Santoro N: The menopausal transition. Am J Med. 2005, 118:8-13. 10.1016/j.amjmed.2005.09.008
40. Delamater L, Santoro N: Management of the perimenopause. Clin Obstet Gynecol. 2018, 61:419-32.
10.1097/GRF.0000000000000389
41. Soares CN: Depression during the menopausal transition: window of vulnerability or continuum of risk? .
Menopause. 2008, 15:207-9. 10.1097/gme.0b013e31816381e9
42. Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL: Risk for new onset of depression during the
menopausal transition: the Harvard study of moods and cycles. Arch Gen Psychiatry. 2006, 63:385-90.
10.1001/archpsyc.63.4.385
43. Freeman EW, Sammel MD, Lin H, Nelson DB: Associations of hormones and menopausal status with
depressed mood in women with no history of depression. Arch Gen Psychiatry. 2006, 63:375-82.
10.1001/archpsyc.63.4.375
44. Harlow BL, Wise LA, Otto MW, Soares CN, Cohen LS: Depression and its influence on reproductive
endocrine and menstrual cycle markers associated with perimenopause: the Harvard Study of Moods and
Cycles. Arch Gen Psychiatry. 2003, 60:29-36. 10.1001/archpsyc.60.1.29
45. Harlow BL, Cramer DW, Annis KM: Association of medically treated depression and age at natural

2021 Padda et al. Cureus 13(7): e16532. DOI 10.7759/cureus.16532 8 of 10

 menopause. Am J Epidemiol. 1995, 141:1170-6. 10.1093/oxfordjournals.aje.a117390
46. Shea AK, Sohel N, Gilsing A, Mayhew AJ, Griffith LE, Raina P: Depression, hormone therapy, and the
menopausal transition among women aged 45 to 64 years using Canadian Longitudinal Study on aging
baseline data. Menopause. 2020, 27:763-70. 10.1097/GME.0000000000001540
47. Georgakis MK, Thomopoulos TP, Diamantaras AA, Kalogirou EI, Skalkidou A, Daskalopoulou SS, Petridou
ET: Association of age at menopause and duration of reproductive period with depression after menopause:
a systematic review and meta-analysis. JAMA Psychiatry. 2016, 73:139-49.
10.1001/jamapsychiatry.2015.2653
48. Bove R, Secor E, Chibnik LB, Barnes LL, Schneider JA, Bennett DA, De Jager PL: Age at surgical menopause
influences cognitive decline and Alzheimer pathology in older women. Neurology. 2014, 82:222-9.
10.1212/WNL.0000000000000033
49. Walker MH, Coffey W, Borger J: Menorrhagia. StatPearls [Internet]. StatPearls Publishing, Treasure Island,
FL; 2021.
50. Cohen SL, Vitonis AF, Einarsson JI: Updated hysterectomy surveillance and factors associated with
minimally invasive hysterectomy. JSLS. 2014, 18: 10.4293/JSLS.2014.00096
51. Strine TW, Chapman DP, Ahluwalia IB: Menstrual-related problems and psychological distress among
women in the United States. J Womens Health (Larchmt). 2005, 14:316-23. 10.1089/jwh.2005.14.316
52. Greenberg M: The meaning of menorrhagia: an investigation into the association between the complaint of
menorrhagia and depression. J Psychosom Res. 1983, 27:209-14. 10.1016/0022-3999(83)90024-7
53. Ballinger CB: Psychiatric morbidity and the menopause; screening of general population sample . Br Med J.
1975, 3:344. 10.1136/bmj.3.5979.344
54. Sanders KA, Bruce NW: Psychosocial stress and the menstrual cycle . J Biosoc Sci. 1999, 31:393-402.
10.1017/s0021932099003934
55. Rafique N, Al-Sheikh MH: Prevalence of menstrual problems and their association with psychological stress
in young female students studying health sciences. Saudi Med J. 2018, 39:67-73. 10.15537/smj.2018.1.21438
56. Elovainio M, Teperi J, Aalto AM, et al.: Depressive symptoms as predictors of discontinuation of treatment
of menorrhagia by levonorgestrel-releasing intrauterine system. Int J Behav Med. 2007, 14:70-5.
10.1007/BF03004171
57. Boricević Marsanić V, Kusmić E: Menorrhagia and ecchymoses in an adolescent girl treated with sertaline .
Arch Womens Ment Health. 2010, 13:453-4. 10.1007/s00737-010-0171-5
58. Aranth J, Lindberg C: Bleeding, a side effect of fluoxetine . Am J Psychiatry. 1992, 149:412.
10.1176/ajp.149.3.412a
59. Ekinci N, Güneş S, Kalinli M, Ekinci Ö: Sertraline-related amenorrhea in an adolescent . Clin
Neuropharmacol. 2019, 42:99-100. 10.1097/WNF.0000000000000336
60. Sienaert PA, Geeraerts I: Menstrual disturbances during electroconvulsive therapy: the forgotten adverse
effect: case report and review of the literature. J ECT. 2013, 29:58-60. 10.1097/YCT.0b013e3182721270
61. Rasoolzadeh N, Zebardast J, Zolphagari M, Mehran A: Effects of relaxation on primary dysmenorhea among
first year nursing and midwifery female students. Hayat. 2007, 13:23-30.
62. Faramarzi M, Salmalian H: Association of psychologic and nonpsychologic factors with primary
dysmenorrhea. Iran Red Crescent Med J. 2014, 16:e16307.
63. Hartlage SA, Breaux CA, Yonkers KA: Addressing concerns about the inclusion of premenstrual dysphoric
disorder in DSM-5. J Clin Psychiatry. 2014, 75:70-6. 10.4088/JCP.13cs08368
64. Ju H, Jones M, Mishra G: The prevalence and risk factors of dysmenorrhea . Epidemiol Rev. 2014, 36:104-13.
10.1093/epirev/mxt009
65. Rivera-Tovar AD, Frank E: Late luteal phase dysphoric disorder in young women . Am J Psychiatry. 1990,
147:1634-6. 10.1176/ajp.147.12.1634
66. Rodrigues AC, Gala S, Neves Â, Pinto C, Meirelles C, Frutuoso C, Vítor ME: Dysmenorrhea in adolescents
and young adults: prevalence, related factors and limitations in daily living. [Article in Portuguese]. Acta
Med Port. 2011, 24:383-92.
67. Jensen MP, Turk DC: Contributions of psychology to the understanding and treatment of people with
chronic pain: why it matters to ALL psychologists. Am Psychol. 2014, 69:105-18. 10.1037/a0035641
68. Jarvik JG, Hollingworth W, Heagerty PJ, Haynor DR, Boyko EJ, Deyo RA: Three-year incidence of low back
pain in an initially asymptomatic cohort: clinical and imaging risk factors. Spine (Phila Pa 1976). 2005,
30:1541-8. 10.1097/01.brs.0000167536.60002.87
69. Iacovides S, Avidon I, Baker FC: What we know about primary dysmenorrhea today: a critical review . Hum
Reprod Update. 2015, 21:762-78. 10.1093/humupd/dmv039
70. Balık G, Ustüner I, Kağıtcı M, Sahin FK: Is there a relationship between mood disorders and dysmenorrhea? . J
Pediatr Adolesc Gynecol. 2014, 27:371-4. 10.1016/j.jpag.2014.01.108
71. Unsal A, Tozun M, Ayranci U, Orsal O: Connection between dysmenorrhea and depression among a group of
turkish high school female students. Pak J Med Sci. 2012, 28:424-7.
72. Bancroft J, Williamson L, Warner P, Rennie D, Smith SK: Perimenstrual complaints in women complaining
of PMS, menorrhagia, and dysmenorrhea: toward a dismantling of the premenstrual syndrome. Psychosom
Med. 1993, 55:133-45. 10.1097/00006842-199303000-00001
73. Bancroft J, Rennie D, Warner P: Vulnerability to perimenstrual mood change: the relevance of a past history
of depressive disorder. Psychosom Med. 1994, 56:225-31. 10.1097/00006842-199405000-00008
74. Pedrón-Nuevo N, González-Unzaga LN, De Celis-Carrillo R, Reynoso-Isla M, de la Torre-Romeral L:
Incidence of dysmenorrhea and associated symptoms in women aged 12-24 years. [Article in Spanish] .
Ginecol Obstet Mex. 1998, 66:492-4.
75. Apkarian VA, Hashmi JA, Baliki MN: Pain and the brain: specificity and plasticity of the brain in clinical
chronic pain. Pain. 2011, 152:49-64. 10.1016/j.pain.2010.11.010
76. Hartlage SA, Freels S, Gotman N, Yonkers K: Criteria for premenstrual dysphoric disorder: secondary
analyses of relevant data sets. Arch Gen Psychiatry. 2012, 69:300-5. 10.1001/archgenpsychiatry.2011.1368
77. Borenstein J, Chiou CF, Dean B, Wong J, Wade S: Estimating direct and indirect costs of premenstrual
syndrome. J Occup Environ Med. 2005, 47:26-33. 10.1097/01.jom.0000150209.44312.d1

2021 Padda et al. Cureus 13(7): e16532. DOI 10.7759/cureus.16532 9 of 10

 78. Gehlert S, Song IH, Chang CH, Hartlage SA: The prevalence of premenstrual dysphoric disorder in a
randomly selected group of urban and rural women. Psychol Med. 2009, 39:129-36.
10.1017/S003329170800322X
79. Taylor DL, Mathew RJ, Ho BT, Weinman ML: Serotonin levels and platelet uptake during premenstrual
tension. Neuropsychobiology. 1984, 12:16-8. 10.1159/000118103
80. Rapkin AJ, Edelmuth E, Chang LC, Reading AE, McGuire MT, Su TP: Whole-blood serotonin in premenstrual
syndrome. Obstet Gynecol. 1987, 70:533-7.
81. Bethea CL: Regulation of progestin receptors in raphe neurons of steroid-treated monkeys .
Neuroendocrinology. 1994, 60:50-61. 10.1159/000126719
82. Delgado PL, Miller HL, Salomon RM, et al.: Tryptophan-depletion challenge in depressed patients treated
with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant
action. Biol Psychiatry. 1999, 46:212-20. 10.1016/s0006-3223(99)00014-1
83. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
(DSM-5). American Psychiatric Association, Arlington, VA; 2013. 10.1176/appi.books.9780890425596
84. Uguz F, Sahingoz M, Kose SA, et al.: Antidepressants and menstruation disorders in women: a cross-
sectional study in three centers. Gen Hosp Psychiatry. 2012, 34:529-33. 10.1016/j.genhosppsych.2012.03.014
85. Hantsoo L, Epperson CN: Premenstrual dysphoric disorder: epidemiology and treatment . Curr Psychiatry
Rep. 2015, 17:87. 10.1007/s11920-015-0628-3
86. Andrade C, Sandarsh S, Chethan KB, Nagesh KS: Serotonin reuptake inhibitor antidepressants and abnormal
bleeding: a review for clinicians and a reconsideration of mechanisms. J Clin Psychiatry. 2010, 71:1565-75.
10.4088/JCP.09r05786blu
87. Kim S, Park YM: Serum prolactin and macroprolactin levels among outpatients with major depressive
disorder following the administration of selective serotonin-reuptake inhibitors: a cross-sectional pilot
study. PLoS One. 2013, 8:e82749. 10.1371/journal.pone.0082749
88. Lai J, Xu D, Peterson BS, Xu Y, Wei N, Zhang M, Hu S: Reversible fluoxetine-induced hyperthyroidism: a
case report. Clin Neuropharmacol. 2016, 39:60-1. 10.1097/WNF.0000000000000116
89. Özkan HM: Duloxetine associated galactorrhea and hyperprolactinemia: a case report. [Article in Turkish] .
Turk Psikiyatri Derg. 2020, 31:294-6. 10.5080/u23918
90. Zhou S, Chan E, Pan SQ, Huang M, Lee EJ: Pharmacokinetic interactions of drugs with St John's wort . J
Psychopharmacol. 2004, 18:262-76. 10.1177/0269881104042632
91. Izzo AA: Drug interactions with St. John's Wort (Hypericum perforatum): a review of the clinical evidence .
Int J Clin Pharmacol Ther. 2004, 42:139-48. 10.5414/cpp42139
92. Michael ST: Electric shock treatment and the menstrual cycle . AMA Arch Neurol Psychiatry. 1954, 71:189-
207. 10.1001/archneurpsyc.1954.02320380064008
93. Michael ST: Menstrual disturbances during electric shock treatment; relation to diagnosis and clinical
improvement. Psychiatr Q. 1956, 30:63-72. 10.1007/BF01564328

2021 Padda et al. Cureus 13(7): e16532. DOI 10.7759/cureus.16532 10 of 10