PHYSIOLOGY OF THE FEMALE REPRODUCTIVE
The menstrual cycle involves
the monthly preparation of the female genital tract for fertilization of an ovum
and for implantation of the embryo into the lining of the uterus. Menstrual
cycle changes are mediated by hormones—chemical messengers produced by the
brain, the pituitary gland, and the ovary. The cyclic production of these
hormones gives the menstrual cycle its periodicity, ie, the
regular recurrence of the same events.
Although the menstrual cycle is a
normal physiologic process, symptoms may occur that are distressing or
uncomfortable. Up to 10% of reproductive-age women have severe perimenstrual
symptoms (Logue and Moos, 1986). It is unusual for these symptoms to be a sign
of serious illness, but if they interfere with daily activities or quality of
life, intervention strategies can be considered.
The ovarian cycle
The ovary contains eggs (oocytes)
as well as hormone-producing cells that govern menstrual cycle events and, in
some cases, give rise to menstrual symptoms.
The goal of the ovarian cycle is the
maturation of an oocyte and its release from the ovary at the optimum time for
fertilization. When a girl reaches puberty, her ovaries contain about 200,000
oocytes. Each one is surrounded by ovarian stroma. The oocyte and surrounding
layer of cells comprise a unit called the follicle. The primordial follicle is a
resting phase; some follicles remain in this resting
condition for decades.
woman's reproductive life, a select number of primordial follicles are recruited
for further development. Stimulated by follicle stimulating hormone (FSH)
produced by the pituitary gland, the oocyte matures and follicle cells
proliferate. The primary follicle contains an oocyte surrounded by a single
layer of specialized cells called follicle cells. In the next
step, the secondary follicle has several layers of supporting cells, now called
granulosa cells, surrounding the oocyte. The granulosa cells produce estrogen, a
hormone with many functions including stimulating growth of the uterine lining,
or endometrium, where the embryo will develop if pregnancy occurs. The
endometrium will also give rise to menstrual bleeding if pregnancy does not
In each cycle, a number of
primordial follicles are recruited, but only one, as a rule, will ovulate. Some
follicles stop developing at the secondary stage. The secondary follicles that
continue to develop become antral follicles, having formed a fluid-filled space
called an antrum. Typically, only one dominant antral follicle matures to a
Graafian follicle, a structure with a large antrum that
bulges from the surface of the ovary. The dominant follicle produces most of the
estrogen that circulates in the woman's blood each month.
When the dominant follicle is fully
mature, a pulse of luteinizing hormone (LH) is released from the pituitary,
stimulating rupture of the follicle and release of the oocyte. The oocyte is
picked up by the fallopian tube in which fertilization may occur. The remainder
of the follicle is transformed into a corpus luteum. This structure now produces
primarily progesterone, a hormone that modifies the
endometrium, making it more suitable for implantation and for nourishment of the
early embryo. If fertilization does not occur, the corpus luteum involutes
after about 2 weeks. The resultant drop in progesterone results in bleeding from
The interplay of
hormones responsible for the menstrual cycle is shown in Figure 2. This figure
has been simplified to show only the hormones from the pituitary gland (FSH and
LH) and the ovary (estrogen and progesterone). There are other factors that
modify menstrual cycle hormones. Gonadotropin-releasing hormone (GnRH) is a
short peptide produced by the hypothalamus at the base of the
brain. GnRH stimulates production of FSH and LH by the pituitary. The release of
GnRH is modified by many factors within the central nervous system, and in some
women central nervous system factors such as stress can disrupt the menstrual
cycle by influencing GnRH production.
The uterine cycle
The endometrium undergoes a cycle
of growth and development in tandem with the ovarian cycle. The purpose of the
endometrium is to provide protection and nourishment for the early embryo. After
a menstrual period, the endometrium is reduced to its basal level. Before an
embryo can implant successfully, the endometrium must regrow and become thicker.
Stimulated by estrogen during the first half of the menstrual cycle, endometrial
proliferation involves an increase in both the stroma, or connective tissue, and
the blood vessels and glands of the endometrium.
After ovulation, the appearance of
progesterone causes a change in the endometrium. Proliferation of the lining
stops, the glands show an increase in secretions, and the arterioles become more
tightly coiled. Endometrial gland secretions may play a role in nourishing the
embryo prior to implantation, when the embryo is free within the uterine cavity.
The coiling of the arterioles is important in limiting menstrual bleeding if
fertilization does not occur. The muscle walls of the arterioles constrict when
progesterone levels fall, and this constriction results in ischemia of the
endometrium. In response to this ischemic necrosis, the endometrium falls apart,
resulting in shedding of the lining as the menses. Because the arterioles are
constricted, blood loss during the shedding process is usually only about 60 mL,
although there are large variations among women.
Clinical landmarks of the cycle
The physiologic events of the
menstrual cycle can produce signs and symptoms readily identifiable by the
woman. Estrogen not only results in growth of the endometrium but also in
proliferation and swelling of the duct system in the breast, causing some women
to experience an increase in breast size or sensitivity as the cycle progresses.
Progesterone can also can produce proliferation of breast
glandular tissue, so the second half of the cycle can also be marked by breast
enlargement, tenderness, or lumpiness. Estrogen causes the cervix to produce
copious clear mucus; just prior to ovulation, when estrogen levels are high,
women may note an abundant clear discharge. This cervical mucus protects sperm
deposited in the vagina, and it makes sense that the mucus is the most abundant
just prior to ovulation, when it is most desirable to have viable sperm in the
female genital tract.
experience symptoms around the time of ovulation. Ovulatory pain, which is felt
in one or the other lower abdominal quadrants, may be caused by release of blood
or fluid when the dominant follicle ruptures. The decrease in estrogen around
the time of ovulation may also trigger a small amount of spotting or bleeding
from the uterus.
The most notable
attribute of the reproductive cycle is the menstrual discharge. The occurrence
of regular menstrual bleeding is a reliable clinical indicator that ovulation
has occurred and that the woman is ovulatory. Women who do not ovulate will not
produce progesterone and will not have tightly coiled arterioles in the
endometrium. These women will bleed when the endometrium
proliferates excessively and falls apart because it is too thick. This kind of
bleeding occurs at irregular intervals, and because the arterioles are not
coiled, this so-called anovulatory bleeding can be heavy and prolonged.
Changes in progesterone, estrogen, and
perhaps other hormones of the second half of the cycle can cause other symptoms
prior to menstruation, such as alterations in mood and skin appearance. Women
who have premenstrual symptoms and regular menses are almost certainly
ovulatory. Most ovulatory women, in fact, have premenstrual symptoms that tell
them a menstrual period is coming before a discharge occurs.
In some cases, premenstrual symptoms
are severe and unpleasant. When these symptoms interfere with normal activities
or require medical attention, they are called premenstrual syndrome, or PMS.
There is no clear demarcation between “normal” premenstrual symptoms
and PMS. Designating the woman's condition as PMS occurs when the symptoms cause
enough distress that attention is required. Similarly, symptoms that occur
during the menstrual period itself may be distressing, and there is no clear
demarcation between normal and abnormal menstrual symptoms. Finally, it is
common for some menstrual symptoms to begin prior to the appearance of menstrual
bleeding, and there may be nodistinction between a woman's premenstrual symptoms
and her menstrual symptoms. Therefore, the consideration of menstrual symptoms
necessarily overlaps to some extent the consideration of premenstrual symptoms.
Heavy or prolonged bleeding
bleeding, also called menorrhagia, is sometimes defined as greater than 80 mL
blood loss during a menstrual period. Of course, women do not measure their
menstrual blood loss, so the clinical definition of this problem is more
subjective. Certainly, if a woman has anemia attributable to menstrual blood
loss, it can be argued that she deserves treatment for heavy bleeding whether or
not it bothers her. Prolonged menstrual bleeding is less subjective, being
defined as bleeding in excess of 7 days per cycle; however,
some women are accustomed to shorter bleeding durations and may seek treatment
if their menses duration increases, say, from 3 to 6 days.
In addition, women with heavy
menstrual periods commonly complain of passing blood clots, which can be a
frightening occurrence, particularly if new in onset. All blood will clot, and
it is not unusual for menstrual blood to clot within the uterus. The clot can
dissolve within the uterus, and be liquid again when it passes from the vagina.
Also, typical menstrual discharge contains tissue fluid and
endometrium as well as blood, and these nonblood components do not clot. When
bleeding is heavy or brisk, the clot within the uterus may come out before it
has dissolved, and there may be less tissue fluid and endometrial components in
the menstrual discharge. The appearance of clots, then, is simply a marker of
heavier, more rapid blood loss, rather than having another, more sinister
The cause of heavy or
prolonged menstrual bleeding is usually unknown; however, some women have
diseases that can be associated with bleeding abnormalities. Coagulation
disorders, such as von Willebrand's disease, will sometimes come to attention
for the first time when a girl begins to menstruate and the periods are
unusually heavy. Diagnosis of a coagulation abnormality
requires special laboratory testing.
Other women with heavy or prolonged
bleeding have abnormalities of the lining or the muscle wall of the uterus.
Uterine fibroids (leiomyomata uteri) are benign smooth muscle tumors of the
uterine wall that can distort the endometrial cavity and be associated with
abnormally heavy menstrual bleeding. Polyps, which are fingerlike growths in the
endometrial cavity, can also be associated with heavy
bleeding. Polyps are usually benign, but occasionally contain a cancer. Based on
pelvic examination, uterine fibroids can be suspected if there is enlargement or
irregularity of the uterus. Ultrasound examination (sonography) is often used to
identify fibroids and to evaluate their relationship to the endometrial cavity.
Polyps may also be identified on ultrasound, although they
are often smaller and more difficult to visualize than fibroids. Both fibroids
and polyps involving the endometrial cavity can be identified (and in many cases
removed) by hysteroscopy, a minor surgical procedure in which a telescope is
inserted into the uterus through the cervical canal.
Endometriosis, which occurs when
endometrial tissue grows outside of the endometrial cavity, can be associated
with heavy menstrual bleeding, although the mechanism by which endometriosis
produces this symptom is not known. Adenomyosis, which occurs when endometriosis
involves the muscle wall of the uterus, is also associated with heavy menstrual
bleeding. Endometriosis can be visualized in some instances by looking inside
the peritoneal cavity with a laparoscope. Adenomyosis can be diagnosed using
magnetic resonance imaging (MRI) of the uterus. It is uncommon, however, for
laparoscopy or MRI to be used routinely in the evaluation of heavy menstrual
bleeding because hormonal therapy, which is the mainstay of treatment of
endometriosis and adenomyosis, is also used for treatment of heavy menstrual
bleeding of unknown cause. Hormonal therapy will be discussed in more detail
later in this monograph.
cases, abnormally heavy bleeding or prolonged menses is assumed to be due to
excessive proliferation of the endometrium or inadequate coiling of the spiral
arterioles. Both of these situations might prevail if progesterone production by
the c orpus luteum were inadequate to produce arteriolar changes and to stop
endometrial proliferation. Deficient function of the corpus
luteum is believed to occur more frequently as women age, and episodes of heavy
menstrual bleeding can often take place in the years prior to menopause.
Prostaglandins may also play a role in
regulating menstrual bleeding. Prostaglandin I2 (prostacyclin) is a vasodilator
produced by the endothelial cells of blood vessels. Thromboxane is a
vasoconstricting prostaglandin produced by platelets. Having an appropriate
amount of menstrual bleeding may require the right balance between these two
prostaglandins and perhaps other agents in this class;
abnormalities of prostaglandin availability may be involved in the production of
abnormally heavy menses.
should be made between heavy or prolonged periods and irregular bleeding.
Irregular bleeding implies the lack of a cycle; in other words, a woman may
bleed for 4 days, stop for 2 or 3 days, bleed again for a day or two, and so on.
This so-called “lawless” bleeding can occur when a woman does not
ovulate at all. Under these conditions, the endometrium
proliferates without the countervailing influence of progesterone. When the
endometrium becomes sufficiently thick, it falls apart, and bleeding from the
arterioles may start and stop. Another anovulatory bleeding pattern is a heavy
prolonged episode of bleeding every 2 or 3 months, when the thickened
endometrium falls apart and is discharged in large amounts in one episode,
albeit lasting many days or even weeks. Anovulatory bleeding episodes are not
true menstrual periods, because menstrual periods imply the regular shedding of
the endometrium in an ovulatory cycle. Anovulatory bleeding is a warning sign of
possible endometrial hyperplasia or cancer, conditions that are due to prolonged
stimulation of the endometrium by estrogen without adequate protection from
progesterone. The evaluation and treatment of anovulatory bleeding will not be
considered here; suffice it to say that a history of irregular bleeding is best
evaluated by examination by a gynecologic practitioner and in some cases by more
Menstrual cramps are
extremely common, and most women have developed their own methods for dealing
with this kind of discomfort. Some women, however, have menstrual pain that is
difficult to control and that may interfere with daily functioning. Dysmenorrhea
is the term used for painful periods.
Most menstrual pain is believed to originate in the uterus, mediated by
prostaglandins, particularly by prostaglandin F2alpha, released by degenerating
endometrial cells (Coco, 1999; Deligeoroglou, 2000). The prostaglandins induce
uterine muscle contraction and ischemia.
In some cases, menstrual pain
originates outside the uterus. Endometriosis is a common cause of menstrual
pain, and pain from lesions of endometriosis can originate from wherever the
disease is implanted. At one time, it was believed that endometriosis caused
pain because endometrial implants bleed during the menstrual cycle in response
to hormonal changes that normally occur. Because the endometriosis implants are
in tissues where they don't belong, the abnormally located menstrual blood was
believed to produce irritation and pain. Although this theory is not
implausible, and may describe pain production in some women with endometriosis,
there are other women in whom painful endometriosis exists without evidence of
bleeding from the abnormally located tissue. In addition, endometriosis pain can
occur between, as well as during, menstrual periods.
Other causes of pain, which may not be
gynecologic in origin, can be present in women with menstrual pain. These other
painful conditions may show cyclic variation, and may worsen with the menstrual
period. For example, irritable bowel syndrome may be more symptomatic during
menstrual periods than between them, and some women with irritable bowel
syndrome have symptoms only during their menstrual periods. Other painful
conditions, such as fibromyalgia and interstitial cystitis, may also produce
more symptoms during the menses.
Bloating and breast changes
A sensation of fullness or
bloating may be prominent prior to or during menstruation. The sensation may be
associated with weight gain caused by fluid retention. Fluid retention results
from the mineralocorticoid activity of some of the hormones that increase in the
second half of the menstrual cycle. At one time, the mineralocorticoid activity
was blamed on progesterone. Figure 4 shows why this belief
was held. In the synthesis of steroids by the adrenal gland, progesterone can be
a precursor of aldosterone, the major mineralocorticoid hormone in the body.
Aldosterone secretion results in the retention of sodium and water by the
kidney. It was natural to assume that progesterone produced by the corpus luteum
would also be metabolized to aldosterone; however, progesterone produced by the
corpus luteum is largely metabolized by different pathways and does not get
transformed into mineralocorticoids.
Progesterone, in fact, has
antimineralocorticoid activity, antagonizing the action of natural aldosterone
(Landau et al, 1955; Landau and Lugibihl, 1958, 1961). This antagonism appears
to be at the level of the aldosterone receptor. During the luteal phase of the
cycle, perhaps in response to the progesterone antagonism, plasma levels of
aldosterone increase (Michelakis et al, 1975; Katz and Romfh, 1972). As
progesterone levels decline in the premenstrual days, this anti-aldosterone
effect of progesterone is withdrawn, and sodium and fluid retention can occur.
Some women will gain 5 lbs just before or during the menstrual period, losing
the weight rapidly after it is over.
Breast enlargement and tenderness
around the time of the menstrual period may be due to fluid retention, but may
also be the result of changes in breast tissue associated with estrogen and
progesterone. As indicated above, estrogen stimulates growth of the ductal
elements of the breast, ie, the system of small tubes that carry milk from the
milk-producing glands to the nipple during lactation.
Progesterone stimulates growth of the glandular elements themselves, and that
process is associated with an increase in fluid within the breast tissue. The
net effect is that breast tissue becomes more prominent, lobular, and, in some
Bloating and breast
discomfort are self-limited symptoms without serious medical consequences, but
they are the menstrual cycle effects that women complain about most frequently
(Pullon et al, 1987).
The brain is a hormonally
responsive organ, and changes in behavior and mood over the course of the
menstrual cycle have been documented (Krug et al, 1996). Most investigators have
associated the time around ovulation with an increase in creativity,
flexibility, and sexual interest. It has been postulated that these mental
changes make it more likely that women will respond to or initiate sexual
advances, increasing the likelihood of pregnancy during this fertile time.
These periovulatory changes are
subtle, and can be identified only by sophisticated psychological testing. On
the other hand, many women report negative mood changes around the time of
menstrual bleeding, including depression, anxiety, social withdrawal, hostility,
and irritability. The severity of these negative symptoms varies from one woman
to the next; some barely notice a change while others become
suicidal or homicidal.
Menstrual-associated mood problems
have been given different names over the years. Sometimes called premenstrual
tension, these negative mood symptoms have been gathered together with physical
symptoms such as breast tenderness and bloating under the designation of
premenstrual syndrome (PMS). More recently, the mood disturbance associated
with PMS has been called late luteal phase dysphoric disorder (LLPDD) or
menstrual cycle-related mood disorder (MRMD) or premenstrual dysphoric disorder
Some investigators have
regarded PMS with its associated mood disturbances as a condition that always
ends with the onset of menses. It is clear, however, that there are different
patterns in different women, with some experiencing symptoms that extend well
into the days of menstrual bleeding (Mortola, 1992).
Up to 40% of reproductive-age women
can be diagnosed with PMS, but the incidence of the problem varies with the way
the diagnosis is made (Chihal, 1990). Some have favored a strict definition of
PMS, requiring prospective charting of symptoms over several months in order to
document the cyclic nature of the complaint. It has been determined, for
example, that women are unreliable in deciding on their own
if they have PMS, and it has been said that half of women who diagnose
themselves with PMS are mistaken (Chihal, 1990). This point of view may be
scientifically defensible, but it raises the question of what to do about a
woman who complains of troubling mood problems around her period, but does not
satisfy formal criteria for PMS. This woman surely deserves attention,
regardless of whether or not a formal label can be applied to her symptoms.
One problem in making a diagnosis is
that women who have psychiatric diseases, such as anxiety disorders or
depression, may experience substantial changes in their symptoms at different
parts of their cycle (Mortola, 1992). A woman with depression may only report a
problem right before and during her menstrual period, but on closer questioning
she may never feel normal, even on her so-called good days.
In other words, instead of going from feeling well to feeling depressed, as a
woman with strictly defined PMS does, she may go from feeling depressed to
feeling horribly depressed.
causes mood to change with the menstrual cycle in some women? At one time it was
thought that women with cycle-related mood disorders had abnormal levels of
hormones, and there was a period when supplementing menstrual cycle hormones
such as progesterone was believed to be effective. It is clear that women with
cycle-related mood disorders do not differ in estrogen and
progesterone levels from those without these mood disorders (Rubinow and
Schmidt, 1995). There are some differences in the response of the pituitary
gland to thyrotropin-releasing hormone (TRH) and corticotropin-releasing hormone
(CRH) in women who have cyclic mood disorders and those who don't, but it is not
clear that these differences are clinically important.
It appears more likely that
alterations in central neurotransmitters cause cyclic mood problems. A leading
contender for the central nervous system transmitter responsible for menstrual
mood problems is serotonin, which also plays a role in depression (Rapkin,
1992). Other neurotransmitter chemicals are also likely to be involved. In
experimental animals and women, serotonin metabolism is
affected by ovarian hormones, and in some women, the cycle-associated
alterations in the serotonin economy may be sufficient to result in mood
It is common for women to
experience an increase in oiliness of the skin and hair and an increase in acne
just prior to or during the menstrual period. Some women can tell their
menstrual period is about to begin based on changes in their complexion.
Oily skin and acne reflect an increase
in sebaceous gland activity. The sebaceous glands lubricate the skin and hair.
In acne, there is obstruction of the gland ducts. The fatty sebaceous contents
of the glands become colonized with microorganisms, and the sebaceous gland
contents become irritating to the surrounding skin.
Sebaceous gland activity is increased
by androgens (male hormones), but the blood levels of androgens in women do not
increase around the menstrual period (Steinkampf, 1990). The explanation for the
greater sebaceous activity around the menstrual period may lie not with the
level of androgens but with the counterbalancing estrogens, which are
particularly low just before and during the menstrual period.
Many women with menstrual
discomforts have learned ways of making themselves feel better during this time
of the month; however, many others continue to suffer and would benefit from
advice on how to manage their symptoms. It is common for women to use
nonspecific methods, such as bed rest, heat, and distraction, which they have
learned from their mothers or from friends (Campbell and
McGrath, 1999). While some women receive benefit from such measures, these
methods are often not associated with substantial symptom relief by most women.
A variety of more effective treatments are available; none will be suitable for
all women, but most women can expect to gain relief from some combination of
discussed here include only nonsurgical options. Surgical therapies are
available for women who have not responded to nonsurgical treatments. These
therapies generally involve removal of the ovaries or the uterus or destruction
of the endometrium.
between diet and menses-related symptoms is not very clear. Some women believe
that avoiding salt during the latter part of their cycles reduces bloating or
mastalgia, although no studies have confirmed this theory.
The effect of a low-fat diet on
dysmenorrhea and water retention was tested in a crossover study of 33 women, of
whom 21 completed the trial (Barnard, 2000). Women were assigned to a low-fat
vegetarian diet or their regular diet plus a placebo pill; after 2 months the
women crossed over to the other regimen. The duration of dysmenorrhea was
significantly decreased by the diet from 3.9 to 2.7 days. The
duration of symptoms attributable to water retention decreased significantly
from 2.9 to 1.3 days. The placebo treatment had no effect. Another study also
found a decrease in symptoms associated with water retention during the
premenstrual week and during menses in women given a low-fat diet (Jones, 1987).
The type of fat consumed may also make
a difference in dysmenorrhea. Fish oil, high in omega-3 fatty acids, modulates
prostaglandin production and may have an effect on menstrual cramps. A Danish
survey of 181 women 20 to 45 years of age utilized food-intake diaries and found
that menstrual pain was significantly correlated with a low intake of animal
and fish products and a low omega-3 to omega-6 dietary ratio (Deutch, 1995).
In a crossover study, 42 adolescents
with dysmenorrhea were randomized to placebo or fish oil supplements
(eicosapentaenoic acid 1080 mg, docosahexaenoic acid 720 mg, and vitamin E 1.5
mg); after 2 months the groups were crossed over. As assessed by the Cox
Menstrual Symptom scale, dysmenorrhea symptom scores decreased significantly
(from 69.9 to 44.0) after fish oil treatment; there was no
difference between placebo and baseline (Harel, 1996).
Exercise—A review of
studies on dysmenorrhea and exercise identified seven trials on the subject
(three observational studies and four randomized controlled trials) (Golomb,
1998). All of the randomized controlled trials (two of which compared different
types of exercise and two compared exercise to no exercise) found a reduction in
dysmenorrhea. Two observational studies found a lower
prevalence of dysmenorrhea in regular exercisers; the third (which adjusted
scores for disposition, medication, stress, and mood) found that regular
exercisers had more menstrual symptoms than nonexercisers.
A randomized controlled trial compared
the effects of an hour of aerobic exercise three times per week or of strength
training on premenstrual symptoms in 23 healthy women (Steege, 1993). While
participation in either type of exercise improved many premenstrual symptoms,
the only significant difference between groups was in premenstrual depression,
which was less in the aerobic exercise group. Compared to baseline, the aerobic
exercise group improved in various measures of mood, while the strength-training
group improved in food cravings and in feelings of bloating or abdominal
A survey among 2912 women
on US Navy ships gathered information on weight, height, cigarette smoking,
alcohol consumption, exercise, and menses-related symptoms (including cramps,
intermenstrual bleeding, excessive menstrual frequency, heavy menses, menstrual
bleeding longer than a week, and irregular periods) (Kritz-Silverstein, 1999).
Current cigarette smoking was associated with increased risk
of all menstrual symptoms and cycle disorders. Exercise, obesity, and alcohol
consumption were not consistently related with either menstrual symptoms or
Transcutaneous electrical nerve stimulation—Transcutaneous electrical
nerve stimulation (TENS) has become an accepted treatment for various kinds of
pain, and while it is not commonly used for this purpose, there is evidence that
TENS is effective for dysmenorrhea. In a randomized crossover study, 32 women
with severe primary dysmenorrhea were treated with TENS for
two cycles, sham TENS (ie, the “placebo” control) for one cycle, and
ibuprofen for one cycle (Dawood, 1990). During the TENS and placebo TENS cycles,
ibuprofen 400 mg (up to 1600 mg/day) was allowed. Subjects receiving TENS did
not require ibuprofen or required less ibuprofen than with the two other
treatments. TENS also significantly reduced diarrhea,
menstrual flow, clot formation, and fatigue compared with placebo TENS.
An open, randomized crossover study in
12 women compared the use of TENS stimulation and oral naproxen (500 mg) on
dysmenorrhea and intrauterine pressure (Milsom, 1994). Pain scores were
significantly reduced within 30 to 60 minutes following treatment with TENS and
within 19 to 120 minutes after naproxen administration.
the insertion of fine needles into specific points along nonanatomic energy
meridians in an effort to balance energy, is part of traditional Chinese
medicine. One study of dysmenorrhea compared two acupuncture groups with two
control groups. Eleven women received acupuncture at real acupuncture points, 11
received placebo acupuncture at nonacupuncture points, 10 women continued prior
treatment (standard controls), and 11 continued prior methods but also received
extra office visits (visit control) (Helms, 1987). Both acupuncture groups were
treated for 3 weeks of each month (every week except during menses) for three
menstrual cycles. The proportion of women whose average pain scores were reduced
by one-half after treatment was significantly higher in the real acupuncture
group compared to each of the other groups.
uses manual techniques to adjust spinal vertebrae. While this treatment is more
accepted for back pain or musculoskeletal disorders, it is also used to treat
excessive bleeding or dysmenorrhea. A small dysmenorrhea trial compared
chiropractic manipulation (at least twice a week) in eight women with three
controls (Thomason,1979). Seven of the eight women treated with chiropractic
experienced decreased pain and disability, compared with none of the controls.
In a randomized controlled trial of 45
women with dysmenorrhea, 24 women received spinal manipulative therapy and 21
women received sham manipulation (Kokjohn, 1992). The spinal manipulation group
had less abdominal pain than the sham-treated group and lower scores on a
menstrual distress questionnaire.
medicine is popular for gynecological conditions, including menorrhagia or
dysmenorrhea. Manufacturing processes may not be inspected, however, and the
quality of herbal products may not be uniform. A case of lead poisoning from an
Asian remedy for menstrual cramps (Koo Sar or Koo So pills) was reported in
Connecticut in 1997 (MMWR, 1997). In spite of clinician
concerns about quality control, these products remain popular among women for
the self-treatment of menstrual discomforts.
EVENING PRIMROSE OIL (OENETHERA
Oil from the seeds of
evening primrose is high in gamma-linolenic acid. Black currant seed and borage
seed oil are used interchangeably. EPO is a popular treatment for several
gynecological conditions, including mastalgia. A Welsh case series of 414
patients with either cyclic or noncyclic breast pain found that EPO 3 g daily
equaled bromocriptine in effectiveness, although it was not as effective as
danazol (Gately, 1992). Thirty percent of the danazol group and 35% of the
bromocriptine group reported significant adverse events, compared to 4% of the
EPO group. However, a randomized, double-blind, placebo-controlled crossover
trial of EPO in 27 women with premenstrual syndrome and 22 asymptomatic controls
did not support this effect. The effect of evening primrose oil (12 capsules of
Efamol, containing 4.32 g linoleic acid and 0.54 g gamma-linolenic acid) was
tested on breast swelling and discomfort as well as happiness
and feelings of well-being; depressed feelings and crying spells; irritability
and short temper; headache; fatigue; sexual need and positive feelings toward
sex; energetic feeling; and tension and anxiety. Each treatment was given for
four cycles. Although symptoms in both groups improved over time, EPO had no
beneficial effect over placebo (Collins et al, 1993). A systematic review of
seven placebo-controlled trials of EPO for PMS identified only one other trial
besides Collins that was properly randomized and well controlled. This trial of
38 subjects with at least one symptom of fluid retention and breast discomfort
and two symptoms of mood changes tested eight capsules Efamol
daily; there was no benefit for EPO over placebo (Budeiri, 1996).
ST. JOHN'S WORT (HYPERICUM
St. John's wort is a
popular antidepressant herb. In one study, 19 women took one 300 mg tablet
containing 900 µg hypericin daily for two complete menstrual cycles
(Stevinson, 2000). There were significant improvements in mood, including
anxiety, irritability, depression, and mood swings; there was also a significant
decrease in tender breasts and in complaints of swelling. The dose of St.
John's wort used in this study is one third of the usual dose for depression.
St. John's wort can cause photosensitivity and interacts with numerous drugs.
CHASTE-TREE BERRY (VITEX AGNUS
Chaste-tree berry is an herb
used to treat various gynecologic conditions. An open study of 1634 patients in
Germany with PMS tested the effect of this herb on several symptoms including
mastalgia (Loch, 2000). Compared to baseline, subjects experienced a significant
decrease in pain, tenderness, tension, bloating, and swelling.
Vitamins and minerals
Some alternative medicine
practitioners and consumers believe that vitamin E balances hormone levels and
use it for a variety of conditions, including mastalgia. There is no reasonable
evidence to support this claim. A randomized double-blind study compared d-alpha
tocopherol (400 IU) for three cycles in 46 women (41 completed) on various
premenstrual symptoms (London, 1987). Although a favorable result was claimed,
no significant difference was seen between groups.
Vitamin B6 does not appear to be
helpful in treating mastalgia. A controlled trial of 32 women with mastalgia
tested the effects of vitamin B6 500 mg/day for 4 months. The outcome measure
was improvement or worsening of mastalgia. Almost 60% of subjects in each group
improved; there was no difference between groups (Wyatt et al, 1999).
Another controlled crossover study of
42 hospital patients with severe cyclical mastalgia tested the effects of
vitamin B6 200 mg/day against placebo, each for two cycles. Acetaminophen was
allowed. Subjects were assessed monthly; breast pain and tenderness were rated
on a visual analog scale and chart, and acetaminophen requirement was recorded.
No significant difference was seen between groups on any measures (Smallwood,
Another crossover trial of 32
women with premenstrual symptoms tested the effects of placebo against vitamin
B6 50 mg/day on emotional, somatic, and menstrual symptoms. Each treatment was
given for three cycles (with one washout cycle in between). There was a
beneficial effect of vitamin B6 on depression, irritability, and tiredness, but
not swelling, breast discomfort, cramps, or backache (Doll,
1989). High doses of vitamin B6 can cause neurological symptoms; sensory
neuropathy has been reported in patients taking more than 2000 mg of B6 daily,
but rarely with lower doses (Jacobson et al, 1996).
A randomized, double blind,
placebo-controlled crossover study tested the effect of calcium on menstrual and
premenstrual symptoms (Thys-Jacobs, 1989). Calcium carbonate (1000 mg/day
elemental calcium) was tested in 33 women for three cycles. Calcium treatment
for three cycles significantly reduced abdominal cramps and back pain.
A larger randomized double-blind,
placebo-controlled multicenter trial assessed calcium carbonate (600 mg/day
elemental calcium) in 497 healthy premenopausal women with moderate to severe
premenstrual symptoms (Thys-Jacobs, 1998). After three menstrual cycles, the
calcium group experienced a significant improvement in mood swings, depression,
tension, anxiety, and anger. Improvement was also noted in swelling of
extremities, breast tenderness, abdominal bloating, headache, fatigue, food
cravings, and pain, including lower abdominal pain, generalized aches, and low
Magnesium has been used for
cycle-related mood changes. A double blind, randomized trial of magnesium 360 mg
three times/day during the second half of the cycle found that magnesium
significantly reduced menstrual symptoms (Facchinetti, 1991). Another randomized
double blind, placebo-controlled crossover study compared the effect of 200
mg/day magnesium with placebo on premenstrual symptoms in 38
women for two menstrual cycles (Walker, 1998). In the second month, there were
significant improvements in swelling, weight gain, breast tenderness, and
Nonsteroidal anti-inflammatory drugs —Medications that inhibit
prostaglandin synthesis are known as nonsteroidal anti-inflammatory drugs
(NSAIDs). Many NSAIDs are inhibitors of the enzyme cyclooxygenase (COX). There
are two isoforms of this enzyme, COX-1 and COX-2. Most NSAIDs currently
available inhibit both forms of the enzyme. Because COX-1
inhibition is involved in gastrointestinal and renal toxicity, selective
inhibitors of COX-2 are available for people who cannot tolerate the nonspecific
NSAIDs. COX-2 inhibitors are more costly than nonspecific NSAIDs and do not
appear to be more effective in pain relief than the nonspecific NSAIDs.
NSAIDs are useful in reducing the pain
of dysmenorrhea. Pain relief from NSAIDs can be due to the analgesic effects of
these agents, but is also likely to result from inhibition of prostaglandin
synthesis within the uterus. The effectiveness of NSAIDs in dysmenorrhea depends
on the use of adequate doses of these agents (Hersh et al, 2000). It is also
useful to administer NSAIDs in anticipation of the pain,
prior to synthesis of prostaglandins, as opposed to administering them only
after pain is intense and the bulk of the uterine prostaglandins have already
been synthesized. Table 1 lists some NSAIDs that are sold without a prescription
and prescription-level doses that will be useful for dysmenorrhea.
NSAIDs can also be useful for
excessively heavy menstrual periods and have been shown to reduce menstrual
blood loss by 30% (Anderson et al, 1976). As in pain relief, use of these
medications prior to the onset of heavy bleeding is more likely to be effective
than use after heavy bleeding has started.
Diuretics and agents for
mastalgia—Because bloating and mastalgia are prominent symptoms
associated with menses, many nonprescription remedies for menstrual discomfort
contain diuretics. Pamabrom, for example, is a mild diuretic that is a component
of a popular nonprescription remedy for menstrual discomfort. Other menstrual
discomfort medicines contain caffeine, which also has diuretic
When a prescription
diuretic is used, some clinicians prefer spironolactone at doses of 25 to 200
mg/d (Johnson, 1992). Spironolactone is favored because it is potassium sparing
and is associated with less rebound edema than thiazide diuretics (ACOG, 2000).
The preference for spironolactone may also reflect the underlying increase in
aldosterone that occurs around the time of the menstrual
period. As discussed above, this increase in aldosterone is a response to the
anti-aldosterone effects of progesterone.
Although use of diuretics may be
sufficient to relieve breast pain, other medications with activity on the breast
have been used. Bromocriptine, tamoxifen, and danazol have been used for cyclic
mastalgia (Blichert-Toft et al, 1979; Fentiman et al, 1985; Watts et al, 1987).
Although these medications have been shown to be effective in small studies,
they have not been much more effective than placebo, and
their use has been limited by side effects. Bromocriptine is associated with
dizziness and nausea, tamoxifen can produce hot flashes, and danazol may produce
androgenic effects such as oily skin, acne, and bloating.
medications—Mood disturbances can be among the most disabling of the
symptoms associated with the menstrual cycle. Although women with mood symptoms
before and during menses have been considered by some writers to be highly
responsive to placebo, formal investigations show that only a minority (20%)
have a meaningful or sustained improvement with placebo
treatment (Freeman and Rickels, 1999). Some of the medications that have been
used for these mood disorders are listed in Table 2.
The anxiety and irritability
associated with the menstrual period can be treated with benzodiazepines or with
buspirone (Severino and Moline, 1995; Brown et al, 1998). Benzodiazepines are
often recommended for episodic use, ie, to be taken only when symptoms occur for
a few days each month. There is concern that habitual use of benzodiazepines may
result in dependence and in a withdrawal syndrome with abrupt discontinuation.
Buspirone is a nonbenzodiazepine anxiolytic with which some practitioners
have a greater degree of comfort if frequent or regular use is likely.
Episodic use of anxiolytic
medications—only on those days when symptoms occur—offers the
opportunity to abort uncomfortable symptoms without long-term use of
pharmacologic agents. Some women with menstrual-associated mood problems prefer
this kind of therapy because it is not associated in their minds with the stigma
of long-term use of psychiatric medication.
A number of antidepressant medications
have been used for cyclic mood disorders (Table 2). There appears to be
consensus that serotonin-dominant agents are more effective than
noradrenergic-dominant agents, although controlled comparisons are few in number
(Severino and Moline, 1995; Brown et al, 1998). There have been reports of women
using antidepressant medications only during the second half of
the menstrual cycle, with good effect on menstrual-associated mood disturbance,
but most of these agents are used daily. Some women may therefore decide that
the number of days each month that they have symptoms is too few to warrant
daily use of antidepressant medication.
contraceptives are among the most commonly prescribed medications for menstrual
discomforts. Many of the medications discussed above deal with the symptoms
produced in response to the ovarian hormones. Oral contraceptives address some
of these symptoms, but also suppress normal ovarian hormone production,
replacing it with the oral contraceptive hormones.
Combination oral contraceptives in use
today contain an estrogen and a progestin. Nearly all oral contraceptives
contain ethinyl estradiol as the estrogen. This estrogen is similar to naturally
occurring estradiol produced by the follicle, but the ethinyl group protects the
molecule from degradation in the gastrointestinal tract. Women on ethinyl
estradiol tablets not only are exposed to a potent estrogen
but also experience high estrogen levels in the portal circulation, which goes
from the gastrointestinal tract where the tablets are absorbed, directly to the
liver. The estrogenic activity in the portal circulation results in an increase
in hepatic protein synthesis. Among these hepatic proteins are angiotensinogen,
resulting in an increase in activity of the renin-aldosterone
system (Oelkers, 1996). In the United States, oral contraceptives in widespread
use contain 20 to 35 mg ethinyl estradiol, usually given for 21 days of every
28-day cycle. Although some products contain different estrogen doses at
different parts of the cycle, most contain a level dose during the 21 days of
Oral contraceptives also contain
progestins. The progestin in the pill prevents excessive proliferation of the
endometrium and often produces substantial endometrial atrophy, giving rise to
light and short menstrual bleeding in many women. A number of different
progestins exist. Nearly all of them are derivatives of testosterone, with a
variety of modifications to decrease the androgenicity of the
preparation. One progestin, drospirenone, is a spironolactone analogue, with
antimineralocorticoid and antiandrogenic effects (Muhn et al, 1995; Fuhrmann et
Because the estrogenic
component of most oral contraceptives is the same, there has been considerable
effort to modify the progestin component to optimize oral contraceptive effects.
The older progestins (eg, norethindrone, norgestrel) have considerable
androgenic activity in and of themselves, although administration with the
potent estrogen in the oral contraceptive preparation does
not result in androgenic problems such as oily skin, acne, or lipid
abnormalities in most women. Newer progestins (eg, gestodene, norgestimate,
desogestrel) are largely devoid of androgenic effects, and an oral contraceptive
preparation containing one of these progestins has been approved for the
treatment of acne. It is an interesting side note that the
effect of oral contraceptives on acne may be due to an estrogen-mediated
increase in sex hormone-binding globulin (SHBG), a hepatic protein whose
production is increased by oral estrogens. With increased SHBG levels, there is
more binding of the woman's endogenous testosterone and less free testosterone.
This effect would be expected to have a benefit for acne,
irrespective of the progestin associated with the estrogen. Whether oral
contraceptives containing gestodene, desogestrel, or norgestimate work better
for acne than oral contraceptives containing the same estrogen with an
androgenic progestin is not known.
different products were developed in the past, there was enthusiasm for changing
the progestin dose throughout the 21 steroid-containing days of the cycle. The
so-called multiphasic tablets contained generally the same dose of estrogen
with two or three different doses of progestin as the cycle went on.
Manufacturers of the multiphasic preparations offered a number of reasons why
multiphasic preparations would be better than monophasic forms, but no advantage
in contraceptive effectiveness, health endpoints, or side effects has been
demonstrated among these products in controlled studies. There appears to be no
scientific reason to prefer a multiphasic product to a monophasic one.
The use of oral contraceptives for
menstrual complaints is based on the following observations:
(1) Menstrual periods on oral
contraceptives are often lighter and shorter than menstrual periods off oral
contraceptives. These agents appear to work by inducing endometrial atrophy (a
progestin effect) and by decreasing uterine prostaglandin production.
(2) Endogenous estrogen and
progesterone production are suppressed, possibly leading to a decrease in
symptoms attributed to individual end-organ response to these normal steroids.
To the extent that mood symptoms, for example, are due to effects of endogenous
steroids on brain neurotransmitter metabolism, use of an oral contraceptive will
remove the endogenous steroids as well as the cyclic changes
in endogenous steroid levels. However, oral contraceptives have adverse effects
on mood for some women, and use of an oral contraceptive preparation may worsen
mood rather than improve it.
Cyclic acne will often improve on oral contraceptives, probably due to the
estrogen-associated increase in SHBG. Not all women experience an improvement in
acne on the older oral contraceptives, the progestins of which are either
androgenic or neutral with respect to androgenicity.
(4) Abnormal bleeding or pain
associated with endometriosis or adenomyosis may respond well to oral
contraceptives. The mechanism of response is not known but may involve
progestin-mediated atrophy of the abnormally located endometrial implants.
The one menstrual symptom group that
does not respond well to the older oral contraceptives is bloating and breast
tenderness. These effects are associated with the oral contraceptive estrogen.
Although progesterone, as mentioned above, has anti-aldosterone effects, none of
the testosterone-derived progestins, including the nonandrogenic progestins,
have anti-aldosterone effects.
of drospirenone as an oral contraceptive progestin may offer advantages over the
use of other progestins. Drospirenone has anti-aldosterone and anti-androgenic
effects, as does spironolactone (Muhn et al, 1995; Fuhrmann et al, 1996).
Administration of an oral contraceptive preparation containing ethinyl estradiol
and drospirenone to healthy women has been shown to be associated with small but
significant decreases in body weight and blood pressure (Oelkers et al, 1995).
An increase in serum triglycerides was seen, as has been noted for other oral
contraceptive agents. There was no change in glucose tolerance compared to
placebo. Another study did not show clinically important changes in weight gain
or blood pressure, but found women on a
drospirenone-containing oral contraceptive to have an improvement in mood and
bloating symptoms over their first year of use of the product (Parsey and Pong,
2000). Whether drospirenone-containing oral contraceptives will be more
effective for acne than other oral contraceptives is not known; however, the
anti-androgenic effects of drospirenone give reason for
Serious adverse effects of
oral contraceptives include an increase in thromboembolic phenomena and,
particularly in smoking women, an increase in myocardial infarction and
stroke.There is also an increase in the appearance of hepatic adenomas, which
are very uncommon, and an increase in gallbladder disease.
GnRH agonists—GnRH is a
hypothalamic peptide that stimulates the pituitary gland to release FSH and LH.
In the absence of GnRH activity, minimal FSH and LH are produced, and the ovary
is inactive. GnRH is normally produced in a pulsatile fashion, with a pulse
every 90 minutes or so. The use of GnRH agonist medications in a manner that
results in continual stimulation of the pituitary gland
results in eventual down-regulation of GnRH receptor; ie, the pituitary gland
becomes refractory to the administered GnRH agonist as well as to native GnRH.
The result is a menopause-like state in which there is no cyclic production of
ovarian hormones and no menstrual bleeding.
GnRH agonist therapy is very effective
for menstrual-associated symptoms. Menopausal symptoms, such as hot flashes, and
menopausal effects, such as a loss of bone mineral density, can be controlled by
coadministration of add-back hormone replacement therapy. In other words, just
as naturally menopausal women can be treated with small doses of estrogen and
progestin for symptoms and to prevent bone mineral loss, so too can women on
GnRH agonist therapy (Surrey, 1999). Use of GnRH agonist therapy for
menstrual-associated symptoms is limited largely by cost. In instances where
menstrual symptoms are severe and do not respond to other interventions, GnRH
agonist therapy may be very useful. These medications are indicated for the
treatment of endometriosis, which can be a cause of dysmenorrhea and abnormal
bleeding, but are not indicated for other
The menstrual cycle is a
physiologic process controlled by hormones produced by the pituitary gland and
ovary. Many women have discomforts associated with the menstrual cycle. In some
cases, these discomforts are severe and interfere with normal activities. Breast
tenderness and bloating are the most common menstrual symptoms. Mood
abnormalities can be the most disrupting menstrual symptoms.
Abnormal menstrual bleeding and pain are also important problems in many women.
Hormone levels in women with these menstrual problems are almost invariably
normal. Although menstrual symptoms can be considered a normal part of life, a
number of therapeutic options are available. While no single option works for
all women, most will be able find a treatment strategy that works well for them.