The European Journal of Contraception and Reproductive Health Care 2 (1997) 22P-237

Dysfunctional uterine bleeding and

dysmenorrhea
C. Coll Capdevila
Women’s Health Program of Maresnie, Catalan Institute of Health, Matar6, Barcelona, Spain

ABSTRACT Normal menstruation involves the breakdown, remodelling and repair of the functional
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endometrial layers. Endometrial destruction and regeneration are largely controlled local
factors, that are dependent on the levels of estradiol and progesterone. Prostaglandins and
endothelins appear to be powerful vasoactive substances in the control of menstrual blood
loss. The tissue endothelin concentration may interact with relaxing factors, such as nitric
oxide, prolonging or increasing menstrual blood loss. Disturbances of menstrual bleeding
and dysmenorrhea are a major medical problem not only for women but also for their
families and health services.Management of dysfunctional uterine bleeding is determined by
the needs of the patient: oral contraceptives are used for women of reproductive age with
ovulatory uterine bleeding episodes who also require contraception; they have a strong
progestogenic effect that is evident as early as the first week of pill intake. In the perimenopausal
patient, dysfunctional uterine bleeding may be treated by cyclic progestins with or without
For personal use only.

conjugated equine estrogens; oral contraceptives can also be used in non-smokers who have
no evidence of vascular disease. Dysmenorrhea is defined as a complaint of pain experienced
during or immediately before menstruation. In the pathogenesis of dysmenorrhea,
prostaglandins and arachinodonic acid metabolites play an important role, being elevated in
women with dysmenorrhea. Oral contraceptives are very effective in the treatment of
dysmenorrhea; they act mainly by reducing the levels of the prostaglandins and arachinodonic
acid metabolites. For women reluctant to take oral contraceptives, non-steroidal anti-
inflammatory drugs may be a better option.

KEY W0RDS Dysfunctional uterine bleeding, Dysmenorrhea, Oral contraceptives

INTRODUCTION

Disturbances of menstrual bleeding and dysmenorrhea Endometrial morphology is controlled by several

are major medical and social problems not only for
women but also for their families and health services.
Oral contraceptives can be used as treatment for benign
disturbances of the endometrium. When considering
this action, the progestogen component of the oral
contraceptive plays an important role since progestogens
have their endpoint in the endometrium, promoting
the secretory transformation of the endometrium from
the proliferative phase.
factors that are involved in the process of its destruction
and regeneration. Oral contraceptives will modify the
local growth factors and therefore they can induce an
atrophic endometrium.
Progestogens have their endpoint i n t h e
endometrium promoting the endometrial
transformation. Natural progestins refer t o
endogenously synthesized progestational agents in
humans. They include progesterone and its various

Correspondence: Dr C. Coll Capdevila. Conscll de Cent, 170, 3A, 08015-Barcelona, Spain

229 Accepted 25-12-97

 Dysjiunctional uterine bleeding arid dysmenorrhea
hydroxylated forms (for example, 17a-
hydroxyprogesterone, 20a,P-dihydroxyprogesterone),
pregnenolorie and 17a-hydroxypregnenolone.
Progesterone is the only natural progestin that has
therapeutic importance.
The synthetic progestins are a class of C21 and C19
steroids derived from 14)-nortestosterone derivatives
(estranes and gonanes) arid 17~-hydroxyprogesterone
derivatives (pregnanes).
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ENDOMETRIAL MORPHOLOGY AND
TISSUE BREAKDOWN
Normal menstruation involves the breakdown,
remodelling and repair of the functional endometrial
layers. Endometrial destruction and regeneration are
largely controlled by local factors (Table l),although
the initial trigger comes from falling estradiol and
progesterone concentrations following luteolysis.
Ovarian steroid hormones are known to have
vasoactive effects,and the vessels of the functional layer
For personal use only.
of the endometrium show marked sensitivity to their
influence'. Estrogen causes a fall in uterine vascular
resistance and an increase in endometrial blood flow'.
This effect is lost with the appearance of progesterone.
The actions of ovarian steroid hormones may be
potentiated in dysfunctional uterine bleeding by the
release of various local mediators through an increase
in endometrial estrogen and progesterone receptors in
glandular and stronial tissue".The control of menstrual
bleeding relies to a considerable extent on the timely
and adequate constriction of bleeding vessels.
Prostaglandin and endothelins appear to be powerful
vasoactive substances in the control of menstrual blood
loss, and circulating estrogen and progesterone
concentrations4 regulate their production. Tissue
endotheliri concentrations may interact with relaxing
factors such as endothelium-derived relaxing factor, also
known as nitric oxide5.Disrupted patterns of endothelin
production may prolong or increase menstrual blood
loss, either directly or via nitric oxide production.
Active fibrinolysis within the normal endometrium
and uterine cavity prevents organized clot formation and
the development of intrauterine adhesions. Excessive
estrogen stindates fibrinolysis,and progesterone inhibits
this process by creating a decidual reaction with an
increased concentration of endogenous fibrinolytic
inhibitors6.Mast cells may also play a role in the defective
230 The European Journal
Coll
Table 1 Local factors involved in endometrial destruction
and regeneration
Hydrolytic enzymes released by the lysosomes: matrix
metalloproteinases
lysosomes release hydrolytic enzymes in premenstrual
phase
matrix metalloproteinases act to degrade most
components of the extracellular matrix and are regulated
by ovarian steroid hormones
Locally synthesized endothelins
may be responsible for the vasoconstriction leading to
the onset of tissue breakdown
Endometrial leukocytes: T lymphocytes and macrophages
and other migratory leukocytes
often located near blood vessels in the endometrium,
where they may influence vascular permeability and
integrity
an excessive leukocyte infiltrate has been associated
with copper intrauterine devices
macrophages may release platelet-activating factor and
prostaglandin E, both of which are potent vasodilators
that could augment menstrual blood loss
hemostatic process; they have been shown to degranulate
premenstrually to secrete heparin, histamine and other
substances'. Heparin stimulates endometrial fibrinolysis
via the secretion of tissue plasminogen activator, and
histamine causes endothelial cell contraction, creating
gaps between vascular endothelial cells to allow increased
vascular fluid loss* (Figure 1).
In the uterus, progesterone controls the growth and
differentiation of endometrial and myometrial cells and
regulates a variety of cell functions directly by either
stimulating or inhibiting structural and functional
proteins, but also indirectly by functionally opposing
estradiol action. The secretory proteins as well as the
expression of growth factors and cytokines determine
the endometrial patterns.
Two polypeptide growth factors have recently been
described: the keratinocyte growth factor (KGF, also
known as FGF-7) and the hepatocyte growth factor
(HGF, also known as scatter factor). Both can be
regulated by several factors including steroid hormones.
Progesterone upregulates KGF and estradiol the HGE
The KGF peptide is dramatically increased during the
h e a l phase to levels 50-100-fold higher than in the
follicular phase, and this increase can be similarly
of Cantracepfioit and Reproductive Health Care
 Dysfunctional uterine Lleeding and dysmenorrhea
I Estradiol
and
progesterone
Lysosomes MMP Endothelins PG Leukocytes
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/ Endometrial remodelling
Figure 1 A putative scheme of interactions within the
endometrium during menstruation. Adapted from Fraser
et a/., 19968. MMP, matrix metalloproteinases; PG,
For personal use only.
prostaglandins
induced by progesterone action. HGF was originally
described as a mitogen that facilitates cyclic endometrial
regeneration and participates in estrogen-dependent
endometrial growth'.
During the cycle, HGF expression increases under
estradiol influence and decreases when progesterone
levels rise, even though estradiol levels remain elevated.
This is the typical pattern of an estradiol-dependent
progesterone-antagonized molecule. KGF expression
increases when the progesterone level rises even when
estradiol is absent and decreases when the progesterone
level falls even though estradiol is present; this pattern
is characteristic of a progesterone molecule. A 'yin-
yang' relationship appears to exist during the cycle as
HGF rises when KGF falls and vice versa.
There are several other growth factors that may
interact with KGF in the endometrium. Progesterone
has been shown to increase the levels of several insulin-
like growth factors (IGF) binding proteins and KGF
may act in concert, together with other growth factors,
to mediate progesterone action in the endometrium.
Inhibition of HGF action might inhibit regeneration
of the endometrium during the luteal phase or modify
it. In that sense, the action of the progesterone
The European Journal of Contraception and Reproductive Health Care
Cull
compound in oral contraceptives can be of importance
when there is an alteration of the endometrial
function.
DYSFUNCTIONAL UTERINE
BLEEDING
Disturbances of menstrual bleeding are a major medical
and social problem for women, their families and the
health services.They are relatively common in all age
groups between 10 and 55 years. Menstrual disorders
are the second most common gynecological condition
resulting in hospital referrallo, and affect up to one-
third of women of child-bearing age.
For those women using hormonal contraceptive
methods, minor disturbances of menstrual bleeding
(breakthrough bleeding) are a common occurrence and
represent t h e most frequent reason stated for
discontinuation of progestogen-only contraceptive
methods. Irregular bleeding w i t h hormonal
contraception tends to be light in volume, but may be
frequent, o r prolonged. Women may interpret
prolonged bleeding as heavy, and so they are concerned
by the long-term health effects of extended bleeding
episodes.There are no established methods of regulating
the bleeding without the addition of estrogens;
disturbances of the menstrual bleeding pattern represent
a considerable management problem.
The term 'dysfunctional uterine bleeding' refers to
excessively heavy, prolonged or frequent bleeding
which is caused by pregnancy or any recognizable pelvic
or systemic disease (Figure 2)". Dysfunctional uterine
bleeding is a diagnosis of exclusion, and will apply in
40-60% of cases of excessive menstrual bleeding.
Recent research has not been able to demonstrate close
endometrial morphological correlation with specific
abnormalities of menstrual bleeding, but has pointed
to an increasing number of molecular mechanisms that
may be involved in the occurrence of certain forms of
abnormal uterine bleeding.
Ovarian cycles associated with excessive bleeding
may be ovulatory or anovulatory. Ovulatory bleeding
accounts for 80% of cases12in modern Western society
and tends to be heavy and/or prolonged, but is generally
regular. Anovulatory dysfunctional uterine bleeding is
seen most comnionly at the beginning or at the end of
the reproductive life, and may be irregular and/or
excessive'.
231
 Dysfurictional uterirze bleedirig arid dysmenorrhea
I Abnormal uterine bleeding
I Organic
1
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Reproductive tract disease
I I
Malignant tumors
Complications of pregnancy
Infections
Other benign pelvic disorders
Figure 2 Differential diagnosis of abnormal uterine bleeding
Ovulatory dysfunctional uterine bleeding
For personal use only.
This condition is characterized by excessive menstrual
bleeding, usually at fairly regular intervals and with a
pattern of daily menstrual loss similar to normal menses.
The onset of bleeding coincides with estradiol and
progesterone withdrawal during luteolysis". The
decrease of progesterone levels will induce:
(1) Increased activity of endometrial lysos~mes'~.
(2) Excessive or prolonged tissue degradation due to
activity of matrix nietallopr~teinases~.
( 3 ) Decreased endometrial tissue concentration of
neutral endopeptides and a consequent rise in tissue
concentration of locally synthesized endothelins
that may be responsible for the vasoconstrictiori
leading to the onset of tissue breakdownt5.
(4) Increased number of small veins in the deep
endometrium and inner niyonietriunil6.
In women with ovulatory dysfunctional uterine
bleeding, there is a significant increase in the
endometrial blood flow compared with normal, and
this is seen during the period of raised estradiol
secretion in the follicular phase17. Ovulatory
dysfunctional uterine bleeding is associated with a shift
in the ratio of endometrial vasoconstricting
232
Coll
I
Acute bleeding episode
- Breakthrough bleeding
- Ovulatory
Iatrogenic Systemic diseases
Sex steroids Hypothyroidism
Hypothalamic depressants Cirrhosis
Digitalis, phenytoin Coagulation diseases
Anticoagulants
Intrauterine contraceptive devices
prostaglandin Fza to vasodilatory prostaglandin E?I8and
an increase in the total endometrial concentration of
prostaglandins4. T h e endometrial estrogen and
progesterone receptors in glandular and stromal tissue
may also be potentiated in women with ovulatory
dysfunctional uterine bleeding3.The excessive estrogen
stimulates fibrinolysis, and progesterone inhibits this
process by creating a decidual reaction with an
increased concentration of endogenous fibrinolytic
inhibitorsh.The secretion of heparin-like substances
is also increased and there are probably also local effects
on platelet function, preventing their efficient
aggregation.The most likely candidate for this role is
the excessive generation of myonietrial prostacyclin,
demonstrated in ovulatory dysfunctional uterine
bleeding by Smith and colleagues".
Anovulatory dysfunctional uterine bleeding
This condition tends t o be characterized by
unpredictable, irregular, prolonged and/or excessively
heavy episodes of bleeding. It is much more common
at the extremes of reproductive life and is the only type
of dysfunctional uterine bleeding widely acknowledged.
Many perimenopausal women will experience
anovulatory cycles that make their menstrual experience
quite unpredictable. The type of bleeding that occurs
The EuropeariJournal .f Contraception and Reproductive Health Care
 Dysfunctional uterine trleeding and dysmenorrhea
after a particular anovulatory cycle will depend on the
endometrial effect of the peak, duration and rate of
decline of serum estradiol concentrations, and excessive
bleeding is often associated with simple hyperplastic
changes in the endometrium’. Bleeding may be light
and intermittent, with lowest estradiol concentrations
and proliferative endometrium, and withdrawal
bleeding may even not occur at all if estrogen withdrawal
is gradual. Bleeding can occur a t any time
endocrinologically speaking (when estradiol
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concentrations are falling, stable or even rising) from
endometrium exposed to increased and unopposed
estradiol concentrations”.
Little is known about disturbances in the local
endometrial environment that may lead to irregular
menstrual bleeding in anovulatory dysfunctional uterine
bleeding. Endometrial blood flow rates are variable but
tend to be higher than normal’.This may reflect the
estrogen dominance in anovulatory cycles.
Progestogen-related breakthrough bleeding
For personal use only.
This term was first used for abnormal bleeding
associated with the use of long-acting hormonal
contraceptives”. Breakthrough bleeding is generally
worst during the first few months after starting
progesterone-only contraceptive use, and bleeding
patterns then improve in the long term, as the
continuous progestogen effect becomes increasingly
established with continuous exposure. O n the other
hand, higher relative concentrations of estrogen will
stabilize the endometrium and minimize the incidence
Table 2 Comparison of features of ovulatory and anovulatory dysfunctional uterine bleeding and progestogen-related
breakthrough b!eeding
Ovulafory dysfunctional
uterine bleeding
Cyclic bleeding pattern regular
Daily menstrual loss normal
Hormonal environment normal
Steroid receptor changes unknown
Endometrial vascularity morphology normal?
Vascular fragility normal
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Coll
of breakthrough bleeding, as seen in combined oral
contraceptive pill users.
Any factor that interferes with the relatively constant
circulating concentrations of contraceptive steroids in
users of long-acting methods, such as drug interactions,
may cause breakthrough bleeding.
Table 2 compares the clinical findings between
ovulatory and anovulatory dysfunctional uterine
bleeding and progestogen-related breakthrough
bleeding, and Table 3 compares the main morpho-
logical parameters,
Management of dysfunctional uterine bleeding
The management of dysfunctional uterine bleeding is
determined by the needs of the patient. Oral
contraceptives are used for women of reproductive age
with anovulatory dysfunctional uterine bleeding
episodes w h o also require contraception. Oral
contraceptives with progestogens of the second and third
generation have a strong progestogenic effect that is
displayed as early as the first week of pill intake. The
morphology of the endometrium shows a marked
reduction in the number and the diameter of the
endometrial glands; stromal edema is detected and
mitoses have not been observed in any cases, indicating
that cell division has been inhibited by the
administration of the oral contraceptives”. For women
of reproductive age who want to conceive, clomiphene
citrate can be used.
For the perimenopausal patient, dysfunctional
uterine bleeding may be treated by the administration
Anovulafory dysfunctional Progesfogen-related
uterine bleeding breakthroigh b\eeding
irregular irregular
prolonged prolonged
increased estrogen increased progestogen
exposure
unknown complex
decreased areterioles decreased arterioles
increased thin vessels increased endothelium
increased thin vessels
increased increased
233
 L>y.$inrtiorzal uterine bleedirlg and dysmenorrhea Coll

Table 3 Comparison of endometrial factors associated with ovulatory and anovulatory dysfunctional uterine bleeding and
progestogen-related breakthrough bleeding

Ovularory dysfunctional Anovulatory dysfunctional Progestogen-related

uterine bleeding uterine bleeding breakthrough bleeding

Prostaglandin increased PGE, and PGI, decreased PGE, and PGI, increased PG epoxides
decreased other PG
Relaxing factor normal? increased? unknown
Endothelin vasoconstriction decreased decreased? variable
Growth factors unknown unknown increased
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Fibrinolytic activity increased increased? suppressed?

Endometrial repair normal abnormal? abnormal?

PG, prostaglandin

of cyclic progestin or cyclic conjugated equine estrogens 1 Dysmenorrhea 1

for 25 days with the concomitant administration of
progesterone for days 18-25. The perimenopausal
patient with dysfunctional uterine bleeding who is a Primary Secondary
non-smoker and does not have evidence of vascular ’spasmodic’ ‘congestive’

1 1
For personal use only.

disease may also be treated with a low-dose combination

oral contraceptive.
T h e l o n g -t e rm treatment for women with
ovulatory dysfunctional uterine bleeding is the most
difficult type of dysfunctional uterine bleeding to
manage. For these patients, prolonged progestin use,
oral contraceptives, non-steroidal anti-inflammatory
drugs, antifibrinolytic agents, danazol, and, as a last
resort, gonadotropin releasing hormone agonist, are
part of t h e therapeutic arnianientarium. A
combination of two or niore of these agents is often
required to successfully control the abnornial bleeding.
For patients who no longer desire future fertility and
have associated pelvic pathological disorders or for
those who fail all medical regimens, surgical therapy
may be considered; e i the r hysterectomy or
endometrial ablation has been used?).
DYSMENORRHEA
Dysmenorrhea is defined as a complaint of pain
experienced during o r immediately before
menstruation, hut is frequently associated with a
constellation of other symptoms including headaches,
nausea, vomiting, diarrhea and lethargy. Dysmenorrhea
is a symptom and not a diagnosis. It can be caused by a
variety of conditions, and optimum management
Disrupted biochemical Somatic disturbances
regulation
t
Synthesis of prostaglandins
Imbalance in estrogen/progestogen ratio
Altered release of oxytocin and vasopressin
Figure 3 Differential diagnosis of dysmenorrhea
depends on a precise definition of the symptoms and
an understanding of the probable cause.
It is useful to distinguish ‘primary’ from ‘secondary’
types (Figure 3) as the management for each type usually
differs.The primary type is very common arid typically
‘spasmodic’in nature. Symptoms usually appear around
the onset ofbleeding and only last 8-36 h; the onset of
problems occurs predominantly in adolescents and
young adults, appears after the onset of ovulatory
menstrual cycles, and is associated with an excessive
secretion of prostaglandin F2, from the endometrium.
In contrast, the secondary type is frequently ‘congestive’
or dragging in nature. Symptoms typically appear in
the mid-late luteal phase and last 1-2 weeks; onset
occurs mainly in the mid-late reproductive years, and
genital tract pathology is usually recognizable as the
underlying cause2‘. T h e most frequent cause of
secondary dysmenorrhea is endometriosis.

234 The European]oumal of Contraception and Reproductive Health Care

 Dysfunctional uterine Bleeding and dysmenorrhea Coll

Table 4 Mean and median values of eicosanoids present in the menstrual fluid. Adapted from Bieglmayer eta/., 199526

Mean Median Release rate

Eicosanoid (ng/g blood1 (ng/g blood) (ng/h)

12-HETE 1 1 7 4 f 130 1148 1198

a,‘‘‘ 343 & 46 355 404
Thromboxane B, 2 1 2 f 39 195 21 1
HHT 1 5 8 f 26 110 125
5-HETE 1 1 4 f 12 101 125
15-HETE
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1 0 5 f 10 97 118
Leukotriene B, 56? 8 54 59
PGE, 55k 8 50 64
Deh yd roketostero id 32 f 8 15 29
6-Keto 17k 2 17 20
17P-Estradiol 4 f 1 4 3
Progesterone 4f 1 2 2

12-HETE, 12-hydroxy-eicosatetraenoic acid, PGF, prostaglandin FZa, HHT, 12-hydroxy-heptadecatrienoic acid, PGE,. prostaglandin E,
6-Keto, 6-ketoprostaglandrn F,
For personal use only.

Pathogenesis abundant metabolites of arachinodonic acid are the

lipoxygenase product 12-HETE (12-hydroxy-
Primary dysmenorrhea involves the entire organism and
eicosatetraenoic acid), H H T (12-hydroxy-
the psyche of the suffering woman.The problem is its
heptadecatrienoic acid), the cyclo-oxygenase product
cyclic repetition and everlasting painful expectation.
prostaglandin F,a and others (Table 4).
The pathogenesis is more clarified now but nevertheless
During menses, arachinodonic acid is mainly
not yet completely investigated.There is evidence that
converted to the lipoxygenase product 12-HETE and
underdoniinating role of sexual hormones may cause
to a minor extent to various prostaglandins and other
paracrine sequelae which result in a local increase of
lipoxygenase products. T h e metabolism o f
prostaglandins. The most important factor is the
arachinodonic acid is a complex biological process
rhythmic ischemic reaction due to vasoconstriction in
involved in menstruation, and it is significantly decreased
the small arteries of the uterine wall, causing
by oral contraceptive use. In contrast, an increased
excruciating pains at times.
metabolism of lipoxygenase as well as cyclo-oxygenase
Prostaglandins act locally to?
products is apparently associated with menstrual pain’5,26.
(1) Stimulate smooth muscle in the uterine walls to
contract;
Treatment
(2) Increase the secretion of pepsin, mucus and
hydrochloric acid in the stomach; Modern treatment for dysmenorrhea is pharniaco-
logical. Ther e are two approaches: preventing
(3) Stimulate platelet aggregation to enhance blood ovulation with oral contraceptives or using anti-
clotting;
inflammatory drugs. The mechanisms of action are
(4) Constrict the bronchioles; different (Figure 4).
( 5 ) Induce pain and inflammation;
(6) Induce fever. Oral contraceptives

Arachinodonic acid metabolites, present in menstrual Treatment is usually effective if the combined pill is
fluid, are associated with menstrual pain. The most used; the progesterone-only pill prevents ovulation in

~~

The EuropeanJournal of Contraception and Reproductive Health Care 235

 Dy$unrtional uterine bleeding arid dyswienorrhea Coll

Lipids released from

the membrane of a
damaged cell
- prostglandin E, as well as a reduction of prostaglandin
production. Prostaglandin F2, and thromboxane
B, contract the uterus and the uterine arteries

i
Arachidonic acid
Oral contraceptives (figure 5).

I @-0

Prostaglandin
Prostaglandin inhibitors

b Dysmenorrhea
Non-steroidal anti-inflarrimatory drugs

For women reluctant to take oral contraceptives, non-

steroidal anti-inflammatory drugs may be a better
Figure 4 Oral contraceptives and prostaglandin inhibitors option. These operate by inhibiting the action of an
in the treatment of dysmenorrhea. Adapted from Gould,
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enzyme, cyclo-oxygenase, essential in the biosynthetic

199425
only 4040%)of cycles, exerting its contraceptive effect
mainly by rendering the cervical mucus hostile to
sperm. The combined pill, containing both estrogen
and progesterone, inhibits ovulation in each cycle,
provided that it is taken as instructed.
Oral contraceptives produce a reduction in the
detected concentrations of prostaglandin F2,, 6-
ketoprostaglandin F,,, throniboxane B,, and
For personal use only.
pathway leading from arachidonic acid to prostaglandin
formation (Figure 4).
Several drugs can be taken to relieve dysmenorrhea.
Aspirin is the most widely taken because it can be
obtained without prescription; it is quite effective but
is rapidly metabolized and excreted, so it must be taken
every few hours if the individual is to remain free of
pain. Indomethacin may be effective, but maximum
benefit is reported when it is taken on a regular basis
throughout the week before menstruation".This is not

0Women with dysmenorrhea

Women taking oral contraceptives

n n

Figure 5 Concentrations of eicosanoids and steroids in women with dysmenorrhea and with oral contraceptives. Adapted
from Bieglmayer eta/., 199526.(For abbreviations see Table 4 footnote)

236 T h e Europeanlournal of Contraception and Reproductive Health Care

 Dysfunctional uterine bleeding a n d dysmenorrhea
feasible w h e n the cycle is irregular, w h i c h is likely t o
b e the case in y o u n g girls. Mefenamic acid is widely
prescribed. Its analgesic effect is thought to b e only
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