TRASTORNOS ANÍMICOS EN RELACIÓN A CICLOS BIOLÓGICOS

FEMENINOS
RELACIÓN ESTRÓGENO, DEPRESIÓN Y NEUROTICISMO

En general, la relación entre el estradiol y el humor es una beneficiosa: el estradiol

modula los NT implicados en depresión (5HT, DA, NE, ACTH, cortisol y BDNF),
promueve la neuroplasticidad
y neuroprotección y regula
actividad en regiones
cerebrales implicadas en la
depresión (amígdala y corteza
prefrontal dorsolateral). Los
cambios en los estados
reproductivos y los niveles
fluctuantes o nulos de
estradiol precipitan la
depresión en mujeres
vulnerables. El neuroticismo
(ver módulo 6) y las
condiciones premenstruales
comparten loci pleiotrópicos y
están fuertemente asociados.

Dada su fuerte relación con las emociones

negativas, el neuroticismo se considera por
algunos como el factor más importante
asociado a varias formas de psicopatología y
salud de la conducta. Se sabe que
correlaciona con ciertas variables; es mayor
en individuos de estrato socioeconómico
más bajo y en promedio es
significativamente mayor en mujeres que
en hombres. Sus niveles se disparan en la
adolescencia tardía y bajan moderadamente
en la adultez. En consecuencia, la
menarquia parece ser un evento
temporalmente importante, sugerente de un
rol mediador de hormonas sexuales en la
expresión del neuroticismo, lo que a su vez es
apoyado por la asociación mostrada entre los
estados y condiciones premenstruales (de
causalidad hormonal subyacente) y el
neuroticismo.
Las mujeres con mayores niveles de neuroticismo son más propensas a estar
deprimidas, irritables, hipersensibles a
varios estímulos y fatigadas durante la
fase lútea en relación a las otras fases
del ciclo menstrual. Se ha encontrado
también que las pacientes que padecen
síndrome premenstrual (PMS) y
trastorno disfórico premenstrual
(PMDD) tienen mayores niveles de
neuroticismo en comparación a las
pacientes control. Estudios con gemelos
en Australia encontraron una correlación
genética de 0.62 entre PMS y los score
de neuroticismo. Miller et al. evaluaron
el receptor de estrógeno alfa (ESR-1),
mostrando una diferencia asociada al
neuroticismo dada en las pacientes
pero no en los controles, y que
correspondía a una interacción de
diagnóstico por genotipo, con presencia
del alelo menor de 4 polimorfismos de un
solo nucleótido (SNPs) confinados a un
único locus.
 SÍNDROME PREMENSTRUAL y TNO. DISFÓRICO PREMENSTRUAL (TDPM)

El síndrome premenstrual (PMS) y la variante más grave del trastorno disfórico

premenstrual (PMDD) (también llamado trastorno disfórico de fase lútea tardía en
versiones anteriores del DSM), se caracterizan por la presencia de síntomas físicos y/o
conductuales que ocurren de manera repetitiva en la segunda mitad del ciclo menstrual
y a menudo en los primeros días de la menstruación. La gravedad de los síntomas del
SPM o TDPM lleva a interferencias en algunos aspectos de la vida de la mujer, incluyendo
relaciones sociales, trabajo dentro o fuera del hogar, etc. La manifestación física más
común es la distensión abdominal. La sensibilidad en los senos y los dolores de
cabeza también son comunes. Los síntomas emocionales causan una mayor afectación
que los síntomas físicos.
 DSM-V
TRASTORNO DISFÓRICO PREMENSTRUAL 625.4 (N94.3)

A. En la mayoría de los ciclos menstruales, al menos cinco síntomas han de estar presentes
en la última semana antes del inicio de la menstruación, empezar a mejorar unos días
después del inicio de la menstruación y hacerse mínimos o desaparecer en la semana después de
la menstruación.

B. Uno (o más) de los síntomas siguientes han de estar presentes:

1. Labilidad afectiva intensa (p. ej., cambios de humor; de repente está triste o llorosa, o
aumento de la sensibilidad al rechazo).
2. Irritabilidad intensa, o enfado o aumento de los conflictos interpersonales.
3. Estado del ánimo intensamente deprimido, sentimiento de desesperanza o ideas de
autodesprecio.
4. Ansiedad, tensión, y/o sensación intensa de estar excitada o con los nervios de punta.

C. Uno (o más) de los síntomas siguientes también han de estar presentes, hasta llegar a un total
de cinco síntomas cuando se combinan con los síntomas del Criterio B.
1. Disminución del interés por las actividades habituales (p. ej., trabajo, escuela, amigos,
aficiones).
2. Dificultad subjetiva de concentración.
3. Letargo, fatigabilidad fácil o intensa falta de energía.
4. Cambio importante del apetito, sobrealimentación o anhelo de alimentos específicos.
5. Hipersomnia o insomnio.
6. Sensación de estar agobiada o sin control.
7. Síntomas físicos como dolor o tumefacción mamaria, dolor articular o muscular, sensación
de “hinchazón” o aumento de peso.

Nota: Los síntomas de los Criterios A-C se han de haber cumplido durante la mayoría de los ciclos
menstruales del año anterior.

D. Los síntomas se asocian a malestar clínicamente significativo o interferencia en el trabajo, la

escuela, las actividades sociales habituales o la relación con otras personas (p. ej., evitación de
actividades sociales; disminución de la productividad y la eficiencia en el trabajo, la escuela o en
casa).
E. La alteración NO es simplemente una exacerbación de los síntomas de otro trastorno,
como el trastorno de depresión mayor, el trastorno de pánico, el trastorno depresivo persistente
(distimia) o un trastorno de la personalidad (aunque puede coexistir con cualquiera de estos).
F. El Criterio A se ha de confirmar mediante evaluaciones diarias prospectivas durante al
menos dos ciclos sintomáticos.
(Nota: El diagnóstico se puede hacer de forma provisional antes de esta confirmación.)
G. Los síntomas no se pueden atribuir a los efectos fisiológicos de una sustancia (p. ej., una
droga, un medicamento, otro tratamiento) o a otra afección médica (p. ej., hipertiroidismo).

Es común tener uno o algunos síntomas premenstruales, no obstante, el PMS clínicamente

significativo ocurre en 3 a 8 % de las mujeres y el PMDD en 2% aproximadamente. Estos
diagnósticos se han sobreestimado por la falla en aplicar criterios diagnósticos estrictos; se
han hecho estimados de hasta el 80% para PMS, por criterios de inclusión laxos que reúnen
pacientes con cualquier tipo de síntoma anímico o físico, sin considerar severidad o
incapacidad asociada. El PMS se ha descrito en diversos escenarios culturales, incluso
donde no se está muy al tanto del trastorno, y tasas similares de ocurrencia se han
encontrado en Medio Oriente, Islandia, Kenia, Nueva Zelanda y Asia. Los síntomas
mayormente reportados son hinchazón abdominal, calambres, irritabilidad, mastalgia,
artralgias y lumbalgia.
PATOGÉNESIS
El PMS se gatilla debido a cambios en los esteroides gonadales durante la fase lútea en
mujeres susceptibles, a raíz de la interacción entre los cambios cíclicos entre estos y el
funcionamiento de los neurotransmisores centrales, siendo el más implicado la serotonina,
aunque hay evidencia de un rol de β-endorfina, GABA y el sistema nervioso autónomo
(también se ha observado un rol de la desregulación del Ca).

ESTEROIDES OVÁRICOS
Su importancia se puede observar tras el uso de agonistas de GnRH que conlleva
experimentalmente a una resolución dramática de los síntomas de PMS, pero los cambios
cíclicos no parecieran explicar por sí solos los síntomas, ya que las concentraciones entre
estrógeno y progesterona séricos son similares en mujeres con PMS/PMDD y los controles.

Deficiencies in progesterone, progesterone metabolites (some of which have anxiolytic properties),

and the progesterone receptor have also been proposed as possible mediators of PMS/PMDD.
However, as noted, serum progesterone concentrations are normal in women with PMS. In addition,
serum concentrations of the progesterone metabolites, allopregnanolone and pregnenolone, are
similar in women with PMS compared with normal women [29]. Lastly, blocking the effect of
progesterone in the luteal phase with a progesterone receptor antagonist (mifepristone) does not
alleviate the symptoms of PMS [30].

Although women with PMS have normal concentrations of serum estrogen and progesterone, they
may have an abnormal response to normal hormonal changes. In a double-blind, crossover trial of
women with PMS, for example, 10 women who received leuprolide had a significant decrease in
symptoms compared with women who received placebo [25]. However, subsequent administration of
either estrogen or progesterone in addition to leuprolide resulted in a significant recurrence of
symptoms. In contrast, no changes in mood occurred in 15 control women without PMS who received
the same regimen, or in five women with PMS who were given leuprolide plus placebo
postmenopausal hormone therapy. These findings suggest that gonadal steroids are necessary, but
not sufficient, to cause symptoms of PMS. The biological basis for these findings are related to a 2014
paper exploring genetic pathways for risk. (See 'Risk factors' above.)

NEUROTRANSMISORES
Based upon in vitro data and animal studies, there is evidence that cyclic fluctuations in circulating
estrogen and progesterone cause marked changes in the opioid [31], GABA [32], and serotonin [33]
systems. At one time, it was thought that the symptom constellation of PMS resulted from
steroid-induced changes in the opioid system. Differences in peripheral beta-endorphin levels are
observed in women with PMS compared with controls in the periovulatory and premenstrual phases of
the cycle [34-36]. However, attempts to confirm these peripheral findings with provocative tests to
probe central opiate activity have not been successful [37].

The potential role of the GABAergic system in PMS has not been extensively investigated. However,
in vitro data suggesting this system is modulated by progestin are corroborated indirectly by the
observation that the benzodiazepine alprazolam is effective in treating PMS symptoms [38] (see
"Treatment of premenstrual syndrome and premenstrual dysphoric disorder", section on 'Other
therapies'). In addition, low levels of the progesterone metabolite allopregnanolone, which enhances
GABA-A receptor function and possesses anxiolytic effects, was thought to play an effect [39]. Data
on whether serum allopregnanolone concentrations differ between symptomatic and asymptomatic
women conflict [29,39].
At the present time, the evidence is most supportive for a major role of serotonin in the etiology of
PMS. This can be illustrated by the following findings:

●Patients with PMS, when compared with controls, have lower whole blood serotonin and platelet
serotonin uptake and imipramine binding during the luteal phase of the menstrual cycle [40-44], and
higher cerebrospinal fluid levels of the serotonin metabolite 5-hydroxyindoleacetic acid as compared
with the dopamine metabolite homovanillic acid [45].

●The symptoms of PMS are ameliorated by the serotonin agonist fenfluramine [46] and aggravated by
acute depletion of the serotonin precursor tryptophan [47]. In addition, serotonin reuptake inhibitors,
such as fluoxetine, are one of the most effective drugs for the treatment of PMS.

●Administration of metergoline, a serotonin antagonist, to fluoxetine-treated women with PMDD

causes a return of mood symptoms [48]. (See "Treatment of premenstrual syndrome and
premenstrual dysphoric disorder".)

Role of vitamins and minerals — Attempts to detect vitamin deficiency in women with PMS have been
unsuccessful, and vitamin therapies are not considered to be an effective therapy.

No differences in vitamin E, vitamin A, or vitamin B6 levels are found [49,50]. However, in one cohort
study, women with high intakes of the B vitamins thiamine and riboflavin from food sources were less
likely to develop PMS than those who had low intakes [51]. No significant associations were seen
between PMS and dietary intake of other B vitamins. Intake of B vitamins from supplements was not
associated with a lower risk of PMS. A number of vitamins and dietary supplements, including vitamin
B6, vitamin E, vitex agnus castus, calcium, and magnesium, have been studied as therapeutic agents
for PMS; however, evidence that any of these, with the exception of vitex agnus castus, is more
effective than placebo is inconsistent. (See "Treatment of premenstrual syndrome and premenstrual
dysphoric disorder", section on 'Other'.)

Several reports suggest that patients with PMS may have lower levels of intracellular magnesium over
the course of the menstrual cycle [52,53], although studies of altered serum levels have produced
inconsistent results [54-56]. One well-conducted study showed an improvement in total PMS symptom
scores and affective symptoms with the administration of magnesium pyrrolidone carboxylic acid (360
mg three times daily in the second half of the menstrual cycle) [57]. However, in other studies,
magnesium was ineffective. (See "Treatment of premenstrual syndrome and premenstrual dysphoric
disorder", section on 'Other'.)
INTRODUCTION —
The premenstrual syndrome (PMS) is characterized by the presence of both physical and
behavioral symptoms that occur repetitively in the second half of the menstrual cycle and
interfere with some aspects of the woman's life. The American Psychiatric Association
defines premenstrual dysphoric disorder (PMDD) as a severe form of PMS in which
symptoms of anger, irritability, and internal tension are prominent.

The management of PMS and PMDD will be reviewed here. The epidemiology,
pathogenesis, clinical manifestations, and diagnosis/differential diagnosis of PMS and
PMDD are discussed separately. (See "Clinical manifestations and diagnosis of
premenstrual syndrome and premenstrual dysphoric disorder" and "Epidemiology and
pathogenesis of premenstrual syndrome and premenstrual dysphoric disorder".)

GENERAL PRINCIPLES
The core symptoms of premenstrual syndrome (PMS) include affective symptoms, such as
depression, irritability, and anxiety, and somatic symptoms, such as breast pain, bloating and
swelling, and headache. The symptom(s) must impair functioning in some way and the
symptom must remit at menses or shortly thereafter. Premenstrual dysphoric disorder
(PMDD) is a more severe form. The diagnostic criteria for PMS and PMDD are reviewed
separately. (See "Clinical manifestations and diagnosis of premenstrual syndrome and
premenstrual dysphoric disorder".)

A clear diagnosis of PMS or PMDD should be established before treatment is

considered. In particular, women must be symptom free during the follicular phase. This can
be best discerned by having a patient chart her mood and physical symptoms daily over the
course of at least one, but ideally two menstrual cycles (figure 1 and table 1). Of note, some
women have low-level symptoms throughout the cycle with worsening premenstrually. This
likely represents a disorder other than PMS or PMDD, such as dysthymic disorder or major
depressive disorder that worsens premenstrually. (See "Clinical manifestations and
diagnosis of premenstrual syndrome and premenstrual dysphoric disorder".)

The treatment goals for patients with premenstrual disorders are to relieve symptoms
and improve functional impairment. A number of approaches, including lifestyle measures
(exercise and relaxation techniques), cognitive behavioral therapy, and medications
(selective serotonin reuptake inhibitors [SSRIs] and/or combined oral estrogen-progestin
contraceptives (COCs) are effective for women with either PMS or PMDD (table 2).

MILD SYMPTOMS
For women with mild premenstrual symptoms that do not cause distress, economic
dysfunction, or social dysfunction, we suggest lifestyle measures such as regular exercise
and stress reduction techniques. Although these interventions are not well studied, they may
be helpful (algorithm 1).

1. Exercise and relaxation techniques — Exercise and stress reduction are beneficial
in general and should be recommended on this basis. Although not rigorously
studied, exercise [1,2] and relaxation [3] may help to alleviate premenstrual
syndrome (PMS) symptoms (table 2). Exercise may be particularly helpful for
 physical symptoms [4]. It is possible that some of the effects of either exercise or
relaxation may be the result of attention and placebo effects.
2. Vitex agnus castus
Vitex agnus castus (chasteberry) is a popular herbal remedy that appears to be an
effective treatment option for women with mild premenstrual symptoms. Overall, vitex
appears to be more effective than placebo for PMS symptoms, while its efficacy for
premenstrual dysphoric disorder (PMDD) is less certain [5]. In a systematic review of
vitex extract trials for PMS (n = 8), only two were eligible for meta-analysis because
of variability in patient populations, definitions of PMS, vitex dosing, and outcome
measures. However, the review and meta-analysis suggests that vitex is
well-tolerated and more effective than placebo for a number of PMS symptoms. Two
trials in women with PMDD (vitex versus fluoxetine) were also analyzed; fluoxetine
was the more effective intervention. However, vitex did show some benefit in one of
the PMDD trials. The most common dosing studied is 20 to 40 mg of vitex extract.
3. Other.
A number of vitamins and dietary supplements, including primrose oil, vitamin B6,
vitamin E, calcium, and magnesium, have been studied as therapeutic agents for
PMS; however, evidence that any of these is more effective than placebo, which has
a 30 percent response rate, is inconsistent (table 2) [6-15].

We currently suggest against the routine use of vitamin B6, high doses of calcium
supplements, or other vitamins given the low-quality evidence and the potential for harm
(peripheral neuropathy with high-dose B6 and an increased risk of renal calculi and possible
risk of heart disease with calcium supplementation). (See "Calcium and vitamin D
supplementation in osteoporosis", section on 'Side effects'.)

MODERATE TO SEVERE SYMPTOMS

Women who meet the criteria for premenstrual syndrome (PMS) or premenstrual dysphoric
disorder (PMDD) including economic or social dysfunction are best served by pharmacologic
or behavioral interventions such as cognitive behavioral therapy (algorithm 1 and table 2)
(see 'Cognitive behavioral therapy' below).

However, before initiating therapy, other conditions with symptoms that can overlap with
PMS/PMDD should be ruled out, including depression or anxiety disorders, substance
abuse, and hypothyroidism.

The two main approaches for initial pharmacotherapy of moderate to severe PMDD include

●Targeting the serotonin system by increasing central serotonergic transmission (selective

serotonin reuptake inhibitors [SSRIs]). Of all the treatment options for PMDD, SSRIs have
the best evidence for efficacy. (See 'Selective serotonin reuptake inhibitors' below.)

●Suppressing the hypothalamic-pituitary-ovarian axis to abolish cyclic changes in

gonadal steroids (combined estrogen-progestin oral contraceptives [COCs],
gonadotropin-releasing hormone [GnRH] agonists). This is typically reserved for women who
have severe symptoms that have not responded to other treatments. COCs may ameliorate
PMS symptoms in general, but they are not better than placebo at decreasing depressive
symptoms experienced premenstrually [16]. (See 'Other therapies' below.)

●In women for whom contraception is not a high priority, we discuss SSRIs first. On the
other hand, if the patient does not have impairing depressive symptoms and contraception is
a high priority, we discuss combination estrogen-progestin contraception first, although some
women may require both a contraceptive agent and SSRIs. (See 'Combined
estrogen-progestin contraception' below and 'Selective serotonin reuptake inhibitors' below.)

Women who do not desire contraception

Selective serotonin reuptake inhibitors — Because of their proven efficacy and safety
profile, we recommend SSRIs for women with premenstrual symptoms that include
socioeconomic dysfunction that have been documented prospectively and who do not desire
hormonal contraception (algorithm 1). (See 'Moderate to severe symptoms' above and
"Clinical manifestations and diagnosis of premenstrual syndrome and premenstrual
dysphoric disorder", section on 'Prospective monitoring with self-rating scale'.)

Clinical trials [17-22] and systematic reviews [23,24] of SSRIs for PMS and PMDD conclude
that these medications are effective. We typically start sertraline, citalopram,
escitalopram, or fluoxetine, as these are extensively studied. Paroxetine is also effective
but is more likely to be associated with weight gain.

A beneficial effect can be expected in the first cycle. If response is suboptimal, the dose
can be increased in the subsequent cycle. SSRI therapy appears to be more effective for
mood symptoms than somatic symptoms [13]. There are no strong predictors of
response to SSRIs in women with PMDD.

Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), is also more effective

than placebo for PMDD [25,26], but we suggest SSRIs as first-line therapy because
venlafaxine is associated with discontinuation symptoms that can be worse than
those seen with SSRIs. (See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology,
administration, and side effects", section on 'Venlafaxine'.)

A tricyclic antidepressant, clomipramine (given either throughout the menstrual cycle or

restricted to the luteal phase), is also more effective than placebo, but we do not suggest its
routine use, because of its side effects (sedation, dry mouth, and weight gain) [27,28]. If it is
used, the starting dose should be 25 mg/day, titrating up to 150 to 200 mg at bedtime.

Regimens — There are three SSRI regimens for the management of moderate to severe
symptoms: continuous daily administration, luteal-phase therapy, or symptom-onset
therapy. The choice of regimen depends upon the pattern and duration of symptoms
(including their predictability) and patient preference. (See 'Choosing a regimen' below.)

Continuous — SSRIs are effective for premenstrual symptoms whether taken continuously
or intermittently [29]. We suggest continuous administration for women with low-level
symptoms present during non-premenstrual intervals. In addition, some women choose this
approach over intermittent regimens for convenience and simplicity. If a woman has severe
physical symptoms, continuous dosing regimens appear more effective than intermittent
regimens [24]. (See 'Choosing a regimen' below.)

Luteal phase therapy — Many women prefer the luteal phase-only regimen, which is
started on cycle day 14 [30]. Therapy is typically discontinued at the onset of menses,
although it may be continued for several additional days in women with a history of
persistent symptoms during menses. This regimen has the advantages of being less
expensive and having fewer side effects. Individual trials [28,31-33] and a meta-analysis [24]
have reported that SSRIs are equally effective for symptom relief whether taken continuously
or only in the luteal phase.

For a woman who chooses this regimen, it is important to ensure that she is asymptomatic
during the follicular phase of the cycle as she will otherwise be undertreated. Higher doses
of the SSRI are needed in some women receiving luteal phase therapy to adequately treat
physical symptoms [34,35]. (See 'Choosing a regimen' below.)

Symptom-onset therapy — Intermittent therapy beginning at the point of symptom onset

until the first few days of menses is effective [36]. In a randomized trial, symptom-onset
therapy was more effective than placebo [37]. (See 'Choosing a regimen' below.)

Choosing a regimen — Deciding whether treatment should be offered continuously

throughout the menstrual cycle, during the luteal phase only, or at symptom onset depends
on a number of factors: (1) clinician assessment that symptoms are present only during the
premenstrual phase of the menstrual cycle versus throughout the menstrual cycle with
premenstrual worsening, (2) patient preference, and (3) predictability of symptom
expression.

●For women with low-level symptoms present during non-premenstrual intervals or with
severe physical symptoms, we suggest daily treatment throughout the menstrual cycle.

●For women with longer intermenstrual intervals, continuous treatment is best since the
onset of symptoms may be unpredictable.

●For women with predictable symptoms that endure for more than a week before the onset
of menses, we suggest a luteal phase regimen.

●For women with symptoms for a week or less who can easily recognize symptom onset, we
suggest symptom-onset therapy.

●If intermittent treatments are ineffective or difficult for patients to follow, continuous
treatment should be offered (algorithm 1).

Dosing — In general, doses used for PMDD are similar to those used for the treatment of
depression. An example of dosing for SSRI regimens in the management of PMDD is shown
for citalopram:

●Continuous daily dosing regimen – The initial dose in cycle one is 10 mg daily. The dose
may be increased over the first month as needed to 20 mg daily. In subsequent menstrual
cycles, further dose increases (eg, in 10 mg increments per menstrual cycle) up to a
maximum of 40 mg/day are sometimes necessary (table 3) [31].

●Intermittent regimens

•Luteal phase dosing regimen – The initial dose in cycle one is 10 mg daily starting on day
14 and continued until the onset of menses. If needed, the dose can increased over the first
month to usual effective dose of 20 mg daily. In a subsequent cycle, a further increase to a
maximum dose of 30 mg/day during the luteal phase is sometimes necessary for optimal
response [31]. Of note, we use a maximum dose of 40 mg/day for continuous regimens, but
only 30 mg/day for intermittent regimens (table 3).

•Symptom-onset dosing regimen – The initial dose in cycle one is 10 mg daily beginning the
day of symptom onset until a few days after the start of menses; over the first month, the
dose may be increased as needed to usual effective dose of 20 mg daily. In subsequent
menstrual cycles, a further increase to the maximum intermittent regimen dose (30 mg/day)
is sometimes necessary for symptom control (table 3).

The suggested dosing for other SSRIs is found in the table (table 3). When starting therapy,
most patients may tolerate the medication better by starting with the minimum effective dose,
for example: fluoxetine 10 mg, sertraline 25 mg (or even 12.5 mg), paroxetine 10 mg,
citalopram 10 mg, and escitalopram 5 to 10 mg (table 3).

For some women, increasing the SSRI dose during the luteal phase is more effective than a
continuous dose throughout the cycle [38].

Adverse effects

●Common side effects – Side effects of SSRIs are dose dependent, occur in approximately
15 percent of patients, and are the most common reason for discontinuing treatment. These
include nausea, headache, insomnia, and decreased libido [24,37]. Nausea, the most
common side effect, usually resolves within four to five days and does not recur if treatment
is given intermittently (luteal phase only). To minimize side effects, we suggest initiating
therapy with a low dose and increasing as needed. (See 'Dosing' above.)

●Sexual side effects – The most problematic side effect of an SSRI may be sexual
dysfunction, including diminished sexual interest, delayed orgasm, and anorgasmia. A dose
reduction may not alleviate this side effect. Women should be informed that this complication
may arise. Sexual function recovers after therapy is stopped. Intermittent (luteal phase)
treatment may reduce these side effects. (See "Sexual dysfunction caused by selective
serotonin reuptake inhibitors (SSRIs): Management".)

●Discontinuation symptoms – Continuous daily (but not intermittent administration) of

sertraline, paroxetine, and venlafaxine for several months followed by sudden treatment
discontinuation can lead to discontinuation symptoms such as dizziness, ringing of the ears,
and mild "body shocks." These withdrawal symptoms are most severe with venlafaxine, a
drug we do not suggest to be a first-line agent. Women should be informed of this possibility
and tapered from medication if possible [39].
Response to therapy — Up to 60 to 70 percent of symptomatic women respond to an SSRI,
but 30 to 40 percent of women do not respond. There are no strong predictors of response
to SSRIs in women with PMDD.

A beneficial effect can be expected in the first cycle. Some women who do not respond to or
tolerate one SSRI may respond to or tolerate a second SSRI, so it is worth attempting this
switch in nonresponders (algorithm 1). Additionally, women who do not respond completely
to luteal phase therapy may benefit from daily therapy, and some women whose response is
not optimal to continuous treatment may do better with luteal phase treatment.

Symptomatic improvement — As noted, 60 to 70 percent of women with PMDD respond to

an SSRI. If continuous SSRI is difficult to tolerate, the patient could try luteal phase-only
treatment.

No improvement — If response is suboptimal, the dose can be increased in the subsequent

cycle. However, lack of response should not be diagnosed until there is no effect after
several menstrual cycles of treatment. SSRI therapy appears to be more effective for mood
symptoms than somatic symptoms [13].

If the SSRI is ineffective, we suggest that women next try a different SSRI (algorithm 1 and
table 2). If a second SSRI is ineffective, we often try a third SSRI before moving to a
second-line therapy. In addition, if multiple SSRIs have been ineffective, we suggest
additional evaluation to ensure that another illness, such as major depression, a substance
use disorder, or another condition, has not been missed. (See 'Combined estrogen-progestin
contraception' below and 'Other therapies' below.)

Duration of therapy — The optimal duration of therapy is unknown. We often continue

therapy for one year and then discuss either a taper and discontinuation of medication
or a trial of intermittent therapy. For women on intermittent therapy, they can try to stop
therapy. Recurrence of symptoms is an indication that treatment should be resumed. Women
with recurrent symptoms typically need treatment until they become pregnant or complete
the menopausal transition.

Women who desire contraception

Combined estrogen-progestin contraception — For women with moderate to severe

nondepressive symptoms who are interested in hormonal contraception, we suggest
treatment with a COC (algorithm 1). This is the simplest way to suppress the
hypothalamic-pituitary-ovarian axis and ovulation. We prefer monophasic pills, as
multiphasic preparations can worsen mood symptoms.

Drospirenone-containing COCs (in particular those with a shortened pill-free interval; four
rather than seven days) are effective and approved for the management of PMDD [40]. We
typically start with a 3 mg drospirenone (DRSP)/20 mcg ethinyl estradiol (EE) COC. If PMDD
symptoms persist and/or there is breakthrough bleeding that does not resolve after three
months, we increase to a 3 mg DRSP/30 mcg EE COC. If PMDD symptoms do not resolve
on the higher estrogen dose, drospirenone-based COC, we often suggest a trial with a
hormonal COC that is continuously administered. In addition, women with PMDD who initiate
COCs should be monitored as some may experience mood worsening with COC treatment
[41]. If symptom relief with the COC monotherapy is incomplete, an SSRI can be added.
(See 'Selective serotonin reuptake inhibitors' above.)

Randomized trials [40,42] and a meta-analysis [43] suggest that a 20 mcg EE/3 mg DRSP
COC with a four-day pill-free interval is more effective than placebo for reducing the
symptoms of PMDD. However, in the meta-analysis, a large placebo effect was seen (36
percent reduction in PMDD symptoms with placebo compared with 48 percent with the COC)
[44]. Other COCs may be effective, but they have not been well studied. In one
meta-analysis of nine trials, COCs improved overall symptoms, but not depression
symptoms of PMS/PMDD, when compared with placebo [16].

Although we sometimes suggest continuous use of a combined COC, data for this approach
are somewhat limited [45-47]. One study observed no benefit of continuous COCs on PMDD
when compared with placebo or a cyclic COC [46]. In contrast, in an analysis of four trials
(three randomized, one open-label) of a continuous COC 20 mcg EE/90 mcg levonorgestrel
(LNG), an overall reduction in PMS and PMDD symptoms was seen compared with placebo
[45]. Women taking the continuous COC experienced higher rates of vaginal bleeding than
the placebo groups (as has been observed in most trials of continuous COCs). This analysis
was limited by inconsistent results across trials and a large placebo effect. In spite of these
limitations, continuous administration of an LNG/EE COC is a reasonable option for women
with PMDD who have not responded to other treatment options such as a COC with
drospirenone and a shortened hormone-free interval. Continuous COCs with progestins
other than levonorgestrel have not yet been studied.

Of concern, drospirenone may be associated with a higher risk of venous thromboembolism

(VTE) than some other progestins. In 2012, the US Food and Drug Administration (FDA)
added revised labeling to COCs containing drospirenone, stating that they may be
associated with a higher risk of VTE when compared with levonorgestrel and some other
progestins. The FDA currently does not advise women to stop drospirenone-containing
COCs, but it does suggest that an individual's risk of VTE be assessed before starting one in
a new COC user. Lastly, the warning notes that the VTE risk with drospirenone is small and
still lower than the risk of VTE during pregnancy. (See "Combined estrogen-progestin
contraception: Side effects and health concerns", section on 'Cardiovascular effects'.)

Other therapies — A number of other medications have been used when either SSRIs
and/or COCs are only partially effective, ineffective, or difficult to tolerate. If the patient is
suffering from severe PMDD not complicated by other illnesses and not responsive to any
SSRIs, we suggest other therapies (table 2).

Cognitive behavioral therapy — Cognitive behavioral therapy (CBT) may provide some
benefit for women with PMDD. A meta-analysis of five randomized trials observed a
reduction in symptoms of anxiety and depression with CBT compared to other interventions
[48]. Other studies have reported a reduction in symptom intensity and distress [49], as well
as an improvement in coping skills [50]. For women with moderate to severe symptoms with
a suboptimal response to pharmacologic treatment, the addition of cognitive behavioral
therapy may be beneficial. (See "Overview of psychotherapies", section on 'Cognitive and
behavioral therapies'.)

GnRH agonists — In women with severe symptoms who have not responded to or cannot
tolerate SSRIs or COCs, we suggest gonadotropin-releasing hormone (GnRH) agonist
therapy with low-dose estrogen-progesterone "add back" therapy as the next step (algorithm
1 and table 2). However, GnRH agonists should not be considered until the patient has first
tried multiple SSRIs and a COC with a shortened pill-free interval or continuous
administration.

The contributory role of ovarian steroids in the pathogenesis of PMDD led to the evaluation
of GnRH agonists in this disorder . The first demonstration of benefit of "medical
oophorectomy" with a GnRH agonist in the treatment of PMS was made in a crossover study
of eight patients [51]. This finding has subsequently been replicated by several other
investigators [52,53]. (See "Epidemiology and pathogenesis of premenstrual syndrome and
premenstrual dysphoric disorder".)

GnRH agonist therapy alone is effective for PMDD [54]. However, GnRH agonists should not
be given without estrogen-progestin add-back therapy to avoid menopausal symptoms and
estrogen-deficiency complications such as bone loss. We typically start with leuprolide
acetate 3.75 mg depot monthly injection. (See "Endometriosis: Long-term treatment with
gonadotropin-releasing hormone agonists".)

The side effects with GnRH agonist when administered alone are related to
hypoestrogenism and are substantial (in particular, hot flashes and loss of bone mineral
density [BMD]) [55]. The long-term use of GnRH agonists is possible with estrogen-progestin
add-back, with no loss of BMD and with continued resolution of symptoms [56,57]. Data
suggest that the addition of estrogen and progestin does not diminish the efficacy of
leuprolide for PMDD [54,58,59]. However, it is essential that estrogen and progestin be given
in a continuous regimen and not in a cyclic fashion, which may reproduce PMS.

For add-back therapy, we suggest continuous daily administration of low-dose estradiol. A

commonly used regimen is daily oral estradiol (1 mg) plus oral micronized progesterone (100
mg). These doses are similar to those used for menopausal hormone therapy. Equivalent
doses of other estrogens or progestins may also be used (estrogen equivalents: oral
estradiol 1 mg = transdermal estradiol 0.05 mg = oral conjugated estrogen 625 mg;
progestin equivalents: oral micronized progesterone 100 mg = oral medroxyprogesterone
acetate 2.5 mg). Some women may experience PMS symptoms from the progestin
add-back, in which case dose adjustments are necessary. (See "Preparations for
menopausal hormone therapy", section on 'Dose equivalents'.)

In some reports, GnRH agonists were less effective for depressive symptoms than for
irritability or physical symptoms [53,60]. However, in one of the authors' experience with
GnRH agonists, this is not the case.

Acupuncture — Data on the efficacy of acupuncture for the treatment of women with PMS
and PMDD are limited [61,62]. However, a systematic review of three trials of acupuncture
versus sham acupuncture suggests that it may improve both mood and physical symptoms
(a 17 and 20 percent absolute reduction when compared with sham acupuncture) [63].
However, there was insufficient evidence to determine if there was a difference in the rate of
adverse events, and acupuncture has never been compared with standard therapies, such
as SSRIs. Therefore, we do not suggest its routine use.

Surgery — Medical therapy of PMDD is usually successful. As a result, surgery (bilateral

oophorectomy/bilateral salpingoophorectomy [surgical menopause]) is considered only as a
last resort (eg, in the very rare refractory cases with severe, disabling symptoms). Three
observational studies found bilateral oophorectomy, usually with concomitant hysterectomy,
to be effective for such patients [64-66].

The following guidelines should be considered before resorting to a surgical approach to

treatment [67]:

●The diagnosis of PMDD must be confirmed with prospective symptom recording

●GnRH agonist therapy must be the only medical approach that has been effective, and it
must have been continuously effective for a minimum of six months

●Tolerance of estrogen (or estrogen-progestin) replacement therapy has been tested during
the GnRH agonist therapy

●Childbearing is complete

●The need for several more years of therapy is anticipated based on the woman's age

Not recommended: Alprazolam — Benzodiazepines, in particular, alprazolam, have been

used in the past as adjunctive therapy for women with PMDD. However, we agree with the
International Society for Premenstrual Disorders and do not suggest the use of alprazolam
for PMDD [68]. Although it may have some benefit when compared with placebo [69], the
risks of potential misuse outweigh the benefits. (See "Prescription drug misuse:
Epidemiology, prevention, identification, and management", section on 'Sedatives-hypnotics'
and "Benzodiazepine use disorder".)

CLIMATERIO Y MENOPAUSIA:
El climaterio corresponde al período de transición entre una etapa fértil y una no fértil de
la mujer, secundario al agotamiento de la reserva ovárica. La ocurrencia de un nuevo
episodio depresivo es más a diagnosis of depression was 2.5 times more likely to occur in
the menopausal transition compared with when the woman was premenopausal (odds ratio
[OR] 2.50; 95% CI 1.25-5.02) [52]. This association is most marked for women with a prior
history of depression or a mood problem. The role of estrogen in the treatment of depression
in perimenopausal women is discussed separately. (See "Treatment of menopausal
symptoms with hormone therapy", section on 'Mood lability/depression'.)
Sleep disturbance — A distressing feature of hot flashes is that they are more common at
night than during the day and are associated with arousal from sleep. However, peri- and
postmenopausal women experience sleep disturbances even in the absence of hot flashes
[55]. The estimated prevalence of difficulty sleeping based upon two longitudinal cohort
studies was 32 to 40 percent in the early menopausal transition, increasing to 38 to 46
percent in the late transition [43,56].

Anxiety and depression symptoms, which are common during the menopausal transition,
may also contribute to sleep disturbances; in one study, they were predictive of subjective
sleep disturbances [57]. In addition, perimenopausal women with hot flashes are more likely
to be depressed [58,59]. (See 'Depression' above.)

Primary sleep disorders are also common in this population. In a report of 102 women ages
44 to 56 years who reported sleep disturbances, 54 (53 percent) had sleep apnea, restless
legs syndrome, or both [57].

Thus, in peri- or postmenopausal women who report sleep disturbances, treating the
vasomotor symptoms may decrease sleep disturbances, but this may not resolve all sleep
problems, as there are many other things that can disturb sleep, such as primary sleep
disorders, anxiety, and depression [57]. (See "Risk factors, comorbidities, and consequences
of insomnia in adults".)

Cognitive changes — While biologic and epidemiologic evidence suggests that estrogen is
important for cognitive function in women, the consequences of hormonal changes during
the menopausal transition, estrogen deficiency after menopause, and the impact of estrogen
therapy remain uncertain.

During the menopausal transition, some women describe symptoms such as forgetfulness,
difficulties with word retrieval, and "brain fog" [60]. However, in a cross-sectional study of
over 200 men and women ages 45 to 55, women in their late reproductive or
perimenopausal years (determined by menstrual status and serum estradiol and FSH
concentrations) outperformed age-matched men in detailed memory tasks [61]. These
apparent sex differences were attenuated in the postmenopausal years. Higher serum
estradiol concentrations in women, a reflection of residual ovarian activity, were associated
with better performance. Thus, some evidence suggests that in early midlife, women appear
to outperform men on memory tasks, but with the onset of menopause and decline in serum
estradiol, any memory advantage diminishes. (See "Estrogen and cognitive function".)

A decline in cognitive function was not observed in the SWAN study, but increases in anxiety
and depression had independent, unfavorable effects on cognitive performance [25]. (See
'Clinical manifestations' above and "Estrogen and cognitive function".)