MENSTRUAL CYCLE– INFL -

UENCED DISORDERS

DR Shaymaa Kadhim Al-

Khafajy

OBJECTIVES

1. Define PMS and PMDD.

2. Describe the criteria of PMDD.

3. Determine the treatment of PMS and PMDD.

4. List other menstrual cycle- Influenced disorders.

The human menstrual cycle is unique as a

physiologic process in that it involves mechanisms

that change on a daily basis rather than remaining

stable. This process of change is carried out

through many hormonal interactions between the

hypothalamic region of the brain, the pituitary

gland, the ovaries.

The follicular phase begins with the onset of menses and culminates in the
preovulatory surge of LH. The luteal phase begins with the onset of the preovulatory
LH surge and ends with the first day of menses.

Initially, at lower levels of estradiol, there is a negative feedback effect on the ready-
release form of LH from the pool of gonadotropins in the pituitary gonadotrophs. As
estradiol levels rise later in the follicular phase, there is a positive feedback on the
release of storage gonado- tropins, resulting in the LH surge and ovulation. The
latter occurs 36 to 44 hours after the onset of this mid- cycle LH surge.

During early follicular development, circulating es- tradiol levels are relatively low.
About 1 week before ovulation, levels begin to increase, at first slowly, then rapidly.
The conversion of testosterone to estradiol in the granulosa cell of the follicle
occurs through an en- zymatic process called aromatization and is depicted in
Figure 4-3. The levels generally reach a maximum 1 day before the midcycle LH
peak. After this peak and before ovulation, there is a marked and precipitous fall.
During the luteal phase, estradiol rises to a maximum 5 to 7 days after ovulation
and returns to baseline shortly before menstruation.

N
Bg Luteal phase is almost always
constant f being la days duratin

before onset f Meuse

ovulation also 14 days before

onsetof next Mense

Menstrual cycle influenced Disorders

IT t a

PMS 1 PMDD Menstrual Monthly Premenst DM

migrine headache epilepsy Asthma

Premenstrual

Syndrome and Premenstrual Dysphoric Disorder

In both PMS and PMDD, patients experience adverse physical, psychological, and

behavioral symptoms during the luteal phase of the menstrual cycle.

Although PMS/PMDD patients and controls do not differ in their average cyclic

levels of sex steroids, gonadotropins, prolactin, or cortisol, there exists a strong

basis to believe that these disorders have a hormonal rather than a purely

psychologic basis.

First, abolition of the menstrual cycle with gonadotropin- releasing hormone (GnRH) agonists, pregnancy, menopause, or spontaneous anovulation provides
symptomatic relief, whereas sequential ovarian hor- mone therapy in hypogonadal patients can induce PMS and PMDD symptoms. Second, cycles with higher
luteal phase levels of estradiol are associated with more severe symptoms.


a a
As many as 80% of regularly ovulating women will

experience some degree of physical and psychological

premenstrual symptomatology. These mild symptoms are

normal, and characteristic of ovulatory cycles. About 5-

10% of these women have moderate symptoms that are

disruptive to daily activities and are said to have PMS. In

less than 5% of women, these symptoms are so severe

that they seriously interfere with usual daily functioning

and personal relationships.

Spectrum of Premenstrual Syndromes

PREMENSTRUAL SYNDROME SEVERITY

Severe (PMDD) PMD D

Moderate (PMS)

J PMI

Mild (PMS)

None

CRITERIA

FOR PREMENSTRUAL DYSPHORIC DISORDER
•

Symptoms seriously interfere with usual functioning/ relationships

•
Premenstrual timing confirmed by menstrual calendar in two consecutive cycles
•

Symptoms resolve after the onset of menses

•
Symptoms are not an exacerbation of another

•disorder

•
At least 5 premenstrual symptoms:

• 1. At least one of the following: Depressed mood Marked anxiety Marked affective lability

Marked irritability

• 2. Other possible symptoms: Decreased interest in regular activities Dif culty concentrating

Lethargy/fatigue

Appetite change/food cravings

Sleep disturbance

Feelings of being overwhelmed Physical symptoms (breast swelling and tenderness,

• bloating, weight gain, edema, or headache)

 laughing crying

so

Ed Ed

criteria of PllmmDD FETRS

Seriously interfers notexacerbation Premenst Resolve 5 mens't

co functions of anotherdis Timing

d after onset sympt.cat
least

Relationships Confirmed by of Menses

Menst calender at least one

in
2g
Consecutive MALI

cycles Depressed mood

Marked Inxiety

Marked Lability

Marked irritability

Another Sympt

Physical sympt

breastswelling Tend

bloating weightgain

edema headache

The physiologic mechanism that results in the

occurrence of PMS/PMDD is not well understood.

Evidence exists that the phenomenon arises, in part, from

atypical metabolism of progesterone that results in lower

levels of the steroid allopregnanolone

e within the central

nervous system. In turn, allopregnanolone

e interacts with

the γ-aminobutyric acid (GABA) and serotonin neurons to

influence the regions of the brain responsible for emotion

and subjective perception. Allopregnenolone is a neuroactive progesterone metabolite that

modu- lates central gamma-aminobutyric acid (GABA) re- ceptors
that modify behavior, emotion, subjective perceptions, and response
to stress.

In addition, the GABA and serotoninergic neurons may

be inherently dysfunctional in PMS/PMDD patients,

especially in those with severe depressive symptoms,

hence the overlap between PMDD and clinical depres-

sion. Major depressive disorder (MDD) persists, however,

on a daily basis for weeks without a relation- ship to the

menstrual cycle. MDDdoesmay be

exacerbated during the

thavePre
n merest Physicalsymptoms
luteal phase of the menstrual cycle and can even coexist

with PMDD in some women. In such cases both PMDD

and MDD need to be treated

TREATMENT

The majority of women who could be characterized as

having PMS should be treated individually and conser-

vatively, with reassurance and mild diuretics for

symptoms such as bloating. Aerobic exercise, reducing

Unsat fat
processed foods, refined sugars and trans-fats are rea-

sonable lifestyle changes to recommend although studies

do not show consistent improvement in PMS symptoms.

The mild anxiety that frequently occurs with PMS may be

treated with agents such as buspirone.

anxiolyticdrug

At present, the most effective therapy studied for women with

PMDD is the SSRI class of antidepres- sants. Fluoxetine taken at

s s
dosages of 20 to 60 mg per day during the luteal phase of the

cycle provides significant symptomatic improvement in 50-60%

of patients.

Sertraline at 50 to 150 mg per day is equally effective.

Other preparations have been effective in at least one randomized

controlled trial. They include calcium carbonate, 1200 mg per day, for

control of mood and behavioral symptoms; spironolactone, 100 mg per

day, for mood and bloating; and buspirone, 25 to 60 mg per day, for

premenstrual anxiety.

Danocrine and bromocriptine are effective for the treatment of cyclic

mastalgia. Pyridoxine (vitamin B6), 50 to 100 mg a day, has

demonstrated mixed results in clinical trials.

usedas alastchoice SIE edema putabodyinto

osteoporosis Pregnany stateor
menopausestate

GnRH agoni ed i h e ogen and p oge in add back o qq.uxepganp.si

approach

minimize hot flashes, are effective in eliminating PMS/PMDD

symptoms. Treatments that have been demonstrated to be ineffective

in randomized controlled trials include oral or vaginal progesterone

u n

and conventional use of combined oral contraceptives. Recent studies

u ei

have shown benefit from the continuous use, or 24 out of 28 day use,

of an oral contraceptive containing the progestin drospirenone.

days of

Menses

Treatment of PMS 1PMDD

PMS PMDD

Conservatively at as SSR I improv So 6 1

Reassurance Fluoxetine

Mild diuretics for bloating sertraline de

Lifestyle changes

Aerobic exec f f processed fodd Calcium carbonate

Trans fats Mood behan symptl

Anxiolytic agent for spironolactone

mild anxiety mood bloating

9 Pirone bus Pirone

Premenst anxiety

Dano crine bromocriptine

cyclic mastalgia

Pyridoxine Vit 1361

mixed results

N.bg 3 GnRH agonists effective forboth PMs 1 BUDD

Add back estrog Progestin thatflashes

as continuous notConventionel use or 24128 day use

of oral CC contain progestin drospirenone is beneficial

Other

Menstrual Cycle Influenced Disorders

MENSTRUAL

MIGRANE HEADACHES

Migraine

headaches, which are believed to result from sequential intracranial

vasoconstriction and vasodilation, are known to be influenced by menstrual

cycling.

They are two to three times more common in women than in men. They

improve

in approximately 80% of patients during pregnancy but recur postpartum.

Usually,

migraines resolve following the onset of the menopause.

Sixty

percent of women who suffer migraine link the occurrence of

their

attacks to the menstrual cycle, and 7% exclusively have

migraines

on the 2 days before or after the onset of menstruation.

Menstrual

migraines usually occur without a preceding aura and are

more

long-lasting and resistant to treatment than migraines occurring

at
other times in the menstrual cycle.

The link between migraine headaches and the hor-

monal changes of the menstrual cycle is believed to be

the phenomenon of estrogen withdrawal. Evidence for

this derives from several observations: first, a small

proportion of women with menstrual migraine have an

upsurge in headache frequency following the pre- there isSurge

following
a

critic drop in estroh
ovulatory estradiol surge; second, exogenous estrogen

reduces the incidence of migraines; and third, exogenous

progesterone may delay the onset of menstruation

without preventing the migraine attacks.

Several

mechanisms have been proposed to explain why estrogen withdrawal

produces

migraine head- aches. They include abnormal platelet aggregation,

central nervous system endogenous opioid dysregulation, and stimulation of

increased

synthesis of prostaglandin in the central nervous system.

Treatment

Tryptamine baseddrugs

Standard treatment of migraine headaches includes triptans, nonsteroidal anti

inflammatory drugs, and ergotamines. Drugs used for the short-term prophy-

laxis of menstrual migraines can be taken 3 to 5 days before and after the onset

of menses. They include nonsteroidal anti inflammatory drugs and triptans.

Menstrual Migraine headaches

as without preceding aura

linked to estrogen withdraw

me

Abnormal CNS endogenous In synthesis of

platelet aggregates opioid dysreg Prostaglandin in

ers

Treatment

for headaches for Prophylaxis

of Menstbig

Triptans Sumatriptan Zolmitriptay

Tf

NSAID
ergot

amines short term long term

prophylaxis prophylaxis

9 Tristan Continue oral

www.J

eIsoredg

contraceptive

after pills 2 4 mouths

onset dMenses

of Sympffreakin

hovmond estrogen Patches between intervals

Protocol 48 hrs before mense confine 3 l days

Several hormonal protocols may also be effective in

preventing menstrual migraines. For short-term

prophylaxis, 100 mcg transdermal estrogen patches

begun 48 hours before anticipated menses and

continued for 3 to 6 days have been shown to be

effective. Continuous oral contraceptive pills for

intervals of 2 to 4 months (with symptomatic

treatment during withdrawal between intervals)

provide long-term prevention of migraines.

MONTHLY

EPILEPSY

Seventy percent of female epileptics report an increased incidence of seizures premenstrually.

14
percent of female epileptics have catamenial epilepsy in which seizures only occur in the

perimenstrual phase of the cycle. e This includes all Varities of epilepsy

Two mechanisms are felt to underlie the phenomenon of catamenial epilepsy. The first is a

direct effect on the neurons of the brain of the reduced progesterone/estradiol ratio.
In vitro, estradiol low- ers the seizure threshold of many varieties of neurons whereas progesterone raises the threshold, making a seizure more likely. Thus, catamenial epilepsy reflects the
effect of a reduced progesterone (and allopregnen- olone) concentration or progesterone-to-estradiol ratio.during the late luteal phase of the menstrual cycle. This correlates well with
several clinical observations: first, some patients with catamenial epilepsy also suf- fer exacerbations during the preovulatory estradiol surge; second, seizure activity is prone to increase in
anovulatory cycles, which may be managed with the use of clomiphene; and third, seizure activity may de- crease in incidence after menopause
A second mechanism explaining this disorder is a reduction in serum levels of anticonvulsants

during the late luteal phase.

This

is believed to be mediated by increased hepatic mono-oxygenase activity, resulting

directly

from reduced sex steroid levels.

primarily progesterone
This is the rationale for the treatment option of closely tracking the menstrual
cycle and de- termining anticonvulsant concentrations in the late luteal
phase, so that drug dosage may be altered when necessary.

Monthly epilepsy

14 af to catamenia epilepsy

Seizures in Perimenst Phase

only

5 Mechanisms

reduced Progesteronedestradid
f serum levels of

ratio anticonvulsants in

late luteal Phase

A hepatic mono oxygenase

activity

withdraw A Migraine

Nib Estrogen Is

Lf increased th or epilepsy
f

Progest estradiol

Pre ovulatory surge d estralid A

risk

a
During

of Seizure

Pre ovulat Surge of estrd 99 risk

following

of Migraine

Treatment of Monthly epilepsy

Progesterone anti convulsant basis

IT

DePo Provera Progestin only Premenst Ganadolone GnRH

Contrac Pill Progest allopregnanolone agonist

Suppositerig analogue

intractable

Taken 21 day d eases

cycle day 3

of neat cycle

Premenstrual Asthma

A Sympt If PEF rate

Treatment

Modify Glucocorticoid Leukotriene antagonist

dosages

Treatment

MedroxyProgesterone
or acetate

The anticonvulsant effect of progesterone is the basis for using Depo-Provera,

progestin-only oral contraceptive pills, or premenstrual progesterone supposi-

tories (50 to 400 mg BID) to reduce seizure activity. Ganaxolone, an

allopregnanolone

e analog taken cycle days 21 through 3 of the next cycle, has also

been found to be an effective seizure prophylactic. GnRH agonist therapy has been

helpful for intractable cases.

PREMENSTRUAL

ASTHMA

Eight

to 40% of female asthmatics report increased symptoms or decreased peak

expiratory ow rates in the premenstrual phase of their cycles.

flowPro- gesterone has bronchodilatory and antiinflammatory effects that may be

responsible for this phenomenon.
Treatment

monitoring of the cycle to modify glucocorticoid or leukotriene antagonist dosage

may be helpful.

DIABETES MELLITUS

A high percentage of women with insulin dependent diabetes mellitus (IDDM)

report changes in glycemic control premenstrually. Most women experience a

worsening of glycemic control, although some report an improvement. Possible

mechanisms for this effect include PMS-induced dietary binges and reduction of

physical activity before and during menses.

Treatment

The suggested management is diet control, exercise, and glucose measurement.

The SSRIs, which are commonly used to treat PMS and PMDD, have been found to

increase insulin resistance which may aggravate glycemic control. Metformin,

which is used in conjunction with insulin for IDDM, acts as an insulin-sensitizing

agent and may smooth out the glycemic control in some women.

DM

in insulin dependent DM

changes in Glycemic control Premenstrually

I s worsening
of Glycemic central
improved

as Treatment
Diet control 1exercise Glucose measured

Metformin

SSRI aggravate glycemic control insulin resistor

Reference:
Hacker & moores Essentials in obstetrics
& gynecology
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