Implementation of the trend marker protocol results in a unique graphical presentation when a hormone and a symptom are plotted as per the day of menstrual cycle. This presentation will indicate behavior of the hormone in relation to the disease independent of whether the hormone levels are normal or abnormal as per the set laboratory limits.

1. Concept of trend markers for menstrual diseases.

2. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 8 0 e2 8 4
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.elsevier.com/locate/apme
Review Article
Concept of trend markers for menstrual diseases
Shilpa Shah
Researcher, University of Mumbai, Fort, Mumbai 400032, Maharashtra, India
article info
abstract
Article history:
Background: For female patients with menstrual cycle related diseases, getting a proper
Received 25 September 2013
diagnosis and treatment is one of the most difficult challenges they face. Many get
Accepted 30 October 2013
incorrectly diagnosed with a variety of conditions due to unavailability of specific test or
Available online 21 November 2013
marker to confirm a diagnosis that can fit their symptoms.
Methods: Current article introduces concept of trend markers for menstrual diseases. It also
Keywords:
suggests methods for application of this concept in routine practice.
Female
Results: Implementation of the trend marker protocol results in a unique graphical presen-
Menstrual diseases
tation when a hormone and a symptom are plotted as per the day of menstrual cycle. This
Hormone
presentation will indicate behavior of the hormone in relation to the disease independent of
Trend markers
whether the hormone levels are normal or abnormal as per the set laboratory limits.
Conclusion: Menstrual diseases are ideal examples where despite of the established hormonal graphics for the three phases of menstrual cycle, there is a need for studying trend
in hormone levels for individual patients with respect to the disease conditions as
demanded by the complexity and variety of symptoms.
Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
1.
Introduction
Menstrual cycle is a biological marker of general health for
females from puberty till menopause. Menstruation is the
cyclic, orderly sloughing of the uterine lining on account of the
interactions of hormones produced by the hypothalamus,
pituitary, and ovaries.1 Almost any menstrual complaint understood in an appropriate vocabulary of suffering could be
labeled a menstrual disorder. The impact of menstruation on
women’s health manifests itself on different levels: living,
education, work and family.2 For female patients with menstrual cycle related diseases, it is a frightful condition. It is an
anticipated trouble that accompanies them every month.
Getting a proper diagnosis and treatment is one of the most
difficult challenges they face. Many get incorrectly diagnosed
with a variety of conditions due to unavailability of specific
test or marker to confirm a diagnosis that can fit their
symptoms. Symptoms of menstrual irregularities can be
similar to and confused with symptoms of other disease
conditions, such as pelvic inflammatory disease, ovarian
cysts, uterine cancer and others. Some of these conditions can
be very serious, even fatal, if left untreated. Further, as patients do not get diagnosed in the earliest stages of their illnesses, their sufferings multiply. In addition, untreated
menstrual irregularities can also lead to serious complications, such as infertility from lack of ovulation, anemia from
prolonged bleeding, endometrial cancer from prolonged build
up of the endometrial lining without menstrual bleeding.3,4
2.
Menstrual diseases
The functional (physiological) bleeding is differentiated
from dysfunctional (hormonal cause) bleeding such as
E-mail address: rescience_5@yahoo.co.in.
0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.apme.2013.10.013

3. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 8 0 e2 8 4
amenorrhea, premenstrual syndrome, premenstrual asthma,
menstrual migraine, arthritis and others.3
2.1.
Amenorrhea
281
patients with cyclic variation in symptoms may have exacerbation at other times during a menstrual cycle, other terms
that have been used to describe this phenomenon include
“menstrual-linked asthma”, “menstrual associated asthma”,
and “perimenstrual asthma”. The fact that adult females are
more severely affected by asthma raises the possibility that
hormonal or biochemical differences related to sex may play a
role in the pathophysiology of asthma.9
Amenorrhea is absence of menses during the reproductive
years. Primary amenorrhea is defined as absence of menses by
age 14 with absence of growth and development of secondary
sexual characteristics or absence of menses by age 16 with
normal development of secondary sexual characteristics.
Possible causes of primary amenorrhea are extreme weight
gain or loss, congenital abnormalities of the reproductive
system, stress, excessive exercises, eating disorders (anorexia
nervosa), polycystic ovarian syndrome, thyroid imbalance,
turner syndrome, imperforated hymen, chronic illness, pregnancy, cystic fibrosis, congenital heart disease, and ovarian or
adrenal tumors.
Secondary amenorrhea is the absence of menses for 3 cycles or 6 months in women who have previously menstruated
regularly. Possible causes of secondary amenorrhea are
pregnancy, post partum pituitary necrosis, breast-feeding,
emotional stress, malnutrition, depression, thyroid imbalance, hyperprolactinemia, rapid weight gain or loss, chemotherapy or radiotherapy, vigorous exercising, kidney failure,
colitis, use of tranquilizers or antidepressants, pituitary,
ovarian, or adrenal turners, and early menopause.
Assessment of amenorrhea is based on history of etiologic
factors, physical examination and related laboratory tests
such as sonogram, pregnancy test, thyroid function test, FSH
(follicle stimulating hormone) level, LH (luteinizing hormone)
level, prolactin level, and laparoscopy. Treatment depends on
the cause.5
Migraine headaches are more common in women and 60e70%
of women with migraines report some relationship with their
menstrual period. Usually there is an increased frequency
before, during and after menses. Menstrual migraine is
thought to occur in about 14% of women.10 There are two
types of menstrual migraine e menstrually related migraine
(MRM) and pure menstrual migraine (PMM). MRM is a headache of moderate-to-severe pain intensity that happens
around the time of a woman’s period and at other times of the
month as well. PMM is similar in every respect but only occurs
around the time of a woman’s period.11 The exact causes of
menstrual migraine are uncertain but evidence suggests there
may be a link between menstruation and migraine due to the
drop in estrogen levels that normally occurs right before the
period starts.12 Menstrual migraine has been reported to be
more likely to occur during a five-day window, from two days
before to two days after menstruation.13 When compared with
migraines that occur at other times of the month, menstrual
migraines have been reported to last longer, be more severe,
occur more often with nausea and vomiting, be more difficult
to treat and occur more frequently.14
2.2.
2.5.
Premenstrual syndrome (PMS)
Premenstrual syndrome (PMS) is a collection of physical, psychological, and emotional symptoms related to a woman’s
menstrual cycle.6 Such symptoms are usually predictable and
occur regularly during the two weeks prior to menses. Generally, symptoms may vanish either before or after the start of
menstrual flow. The combination of symptoms and their intensity vary from woman to woman. More than 200 different
symptoms have been identified, but the three most prominent
symptoms are irritability, tension, and dysphoria.7 Although
the causes of PMS are poorly documented, they probably are
multifactorial. Most women with premenstrual syndrome
experience only a few of the problems. The following symptoms can be attributed to PMS: abdominal bloating, abdominal
cramps, breast tenderness or swelling, stress or anxiety,
trouble falling asleep (insomnia), joint or muscle pain, headache, fatigue, acne, mood swings, worsening of existing skin
disorders, and respiratory (e.g., allergies, infection) or eye
(bulbar disturbances, conjunctivitis) problems.8
2.4.
Arthritis
Rheumatoid arthritis (RA), an inflammatory disease of autoimmune origin, is between two and four times more likely to
strike women than men. Among women, RA is more likely to
develop when reproductive hormonal levels are changing,
such as in the first few months following a pregnancy. A significant trend toward lower risk of RA with longer duration of
breast-feeding is observed. Women who experience irregular
menstrual cycles between the ages of 20 and 35 have an
increased risk of rheumatoid arthritis. The risk of rheumatoid
arthritis increases with age and demonstrates a peak risk at
the typical time of menopause.15
Assessment of premenstrual diseases focuses on detailed
history. Physical examination is necessary to find out if there
are any physical causes for the symptoms. Depending on the
symptom pattern, blood studies, including hormonal investigations are carried out.
3.
2.3.
Menstrual migraine
Hormonal diagnosis
Premenstrual asthma
It has been recognized that many asthmatic women have the
worst of their asthma just a few days before the menstrual
periods. This presentation of asthma in females has been
described as “premenstrual asthma”. However, as some
Suspected diagnosis of menstrual diseases can usually be
made through the type of the menstruation irregularity,
symptoms and the results of the gynecological examinations,
which can then either be confirmed or excluded through a
differentiated laboratory diagnosis. The type of menstrual

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irregularity is not necessarily indicative of the underlying
disorder so the examination of the levels of hormones is
indispensable. Perimenopause, menopause, or other hormone
related diseases such as hypothyroidism and adrenal
exhaustion, all exhibit similar and overlapping symptoms. So
making an accurate diagnosis based on symptoms alone is
very difficult. For example, if a woman presents with hot
flashes clinically one will assume that she requires estrogen
when in actual fact the hot flashes may be due to high cortisol
levels. Further treatment with estrogen in this case might
aggravate the hot flashes leading to excessively high levels of
estrogen which can result in a down regulation of estrogen
receptors. Assuming hormonal conditions in patients without
actual assessment of hormones can cause harm rather than
help. Depending on the assumed disease pattern, not all
hormones need to be examined; rather it can be limited to the
most relevant ones.
The following hormones are determined during the basic
hormone analysis.16
(i)
(ii)
(iii)
(iv)
(v)
(vi)
FSH (follicle stimulating hormone)
LH (luteinizing hormone)
E2 (estradiol)
Progesterone
Prolactin
Testosterone
(vii) Androstenedione
(viii) DHEAS (dehydroepiandrosterone sulfate)
(ix) 17-OH-Progesterone
(x) TSH (thyroid stimulating hormone)
4.
Variables for hormonal assessment
Assessing hormones within the framework of the menstrual
events involve the knowledge of the day of menstruation,
the length of menstruation, the sequential secretion of the
individual hormones (during the course of a menstrual
cycle) and their relationship to one another.17 Measuring
hormone levels in females has several related dependent
variables.
(a) Age: While for teenage patients’ age and time of puberty
are important determinants, for post-puberty females
menstrual phase must be taken into consideration when
investigating the hormone levels. This further can get
affected by history of pregnancy, hormonal therapy for
contraception and pre-ponding or post-ponding the menstrual cycle with help of hormones. For senior females the
related possibility of perimenopause or menopause needs
to be kept in mind.
(b) Day of menstrual cycle: Sex hormone levels do indeed
fluctuate as per the day of menstrual cycle. So the normal
limits for each three phase of menstrual cycle are
different. To determine if the assessed value of hormone is
normal or not, it is mandatory to know that in which phase
of cycle the test is carried out e follicular phase, mid-cycle
peak or the luteal phase. For females suffering from
menstrual diseases it could be difficult at times to quote
their first day of last menstruation period (LMP). For
varying length of menstrual cycle or missed periods these
patient may not be able to inform for sure about the day of
cycle.
(c) Technique: Blood tests, saliva test or urine test can be used
to determine hormone levels. It is important to distinguish
inactive form of the hormone, from its free and biologically
active form. As quite often total hormone levels are within
normal limits but once the free and active levels are tested
deficiencies are identified.
(d) Interpretation: A major problem with hormone testing is
the interpretation of test results. Practitioners with little
experience in hormonal matters often observe results that
lie at the low end of the so called “normal range” and
determine that no hormone imbalance or deficiency exists
thus determine no action is required. A major problem is
that laboratory test “normal” ranges are defined and
standardized according to statistical norms instead of
physiological optimal levels. That is, mathematics rather
than patient symptoms define “normal” hormone levels.
Instead of using “normal” laboratory ranges it would be
ideal to use optimal ranges which as a general rule lie
within the upper one third of the normal laboratory range.
This general rule is only a guide as it does not take the
appropriate balance between certain hormones into account which is also very important. Therefore it is
important that someone with experience and knowledge
on appropriate hormone balance views the test results for
an accurate diagnosis. Often there is a significant
improvement in symptoms when levels at the low end of
the normal range are increased to the upper end of the
normal range with treatment. It should be clarified that
test results must be used in conjunction with signs and
symptoms and not be totally relied upon 100% for a diagnosis and latter on to determine appropriate dosages.
There is always a general optimal physiological level that
can be tried to achieve, however these levels can vary in
some patients and this must be taken into account and can
only be done so by also using symptoms as a guideline.18
It is due to the above variables and wide variety of
symptoms along with enumerable causes that there are no
standard protocols for diagnosis and management of menstrual diseases. Many times the patients suffering from
menstrual diseases are subjected to a great number of
available investigation techniques to know the cause. The
investigative efforts are often a wasted attempt as what is
found at end of detailed investigations is that all the parameters were normal. These patients are often not even
medically registered as being diseased. It is important to
realize that investigating a patient for once may not always
be enough. Even if all investigations appear to be within the
reported normal limits, if the patient continues to complain
and the cause is unidentified, periodic testing and reevaluation of the concerned parameters should be performed before dismissal i.e. their trend should be observed.
Research is required to develop techniques for application of
hormonal investigations in a fashion that would help diagnose the menstrual disorders that more accurately reflect
women’s complaints. Chief objective of such techniques can
be to mark trends in menstruation related hormonal levels

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283
versus clinical symptoms and to provide trend markers for
the menstrual diseases.
temperature graph which indicates ovulation simply highlights the ‘trend marker’ concept. This concept can be applied
in individual patient-oriented ways as under.
5.
(1) In patients having chronic disease complaints which vary
as per the day of menstrual cycle the simple way is to take
detailed history of the patient, correlating the symptoms
for a probable diagnosis, choosing the related hormone/s
and then investigating the patient for that hormone.
Plotting the hormone and a symptom as per the day of
menstrual cycle will produce a unique graphical presentation indicating behavior of the hormone in relation to the
disease. It is important to realize that this understanding
will be independent of whether the hormone levels are
normal or abnormal as per the set laboratory limits.
(2) In patients suffering from intermittent menstrual symptoms the trend marker can be a two-test procedure. Based
on the detailed clinical history and probable diagnosis
choice of hormone/s can be made. Once the hormone selection is done, first estimation can be done immediately
when patient gets diseased and the second estimation of
the same hormone can be made during the disease free
period. Comparison of these two estimations can indicate
the difference in hormone/s with and without disease
irrespective of whether the values are normal or abnormal
as per the set laboratory normal limits. Additionally such
two time estimation is also independent of the day of cycle
or bothering of the menstrual phase. This helps the patient
a lot as diagnostic attempt can start right when the
symptoms are ongoing, rather than waiting for the recommended day of cycle as is usually done during the
standard medical practice.
(3) In patients having amenorrhea plus other symptoms of
menstrual disease the trend marker concept can be applied
after inducing and regularizing the menstrual cycle.
(4) In patients having known hormonal imbalance and menstrual disease the trend markers concept can be applied to
interpret the effectiveness of therapy. For these patients
the therapeutic intervention can be plotted against a
health or disease parameter along with the hormone
which is selected based on the clinical history and probable diagnosis.
(5) Anticipatory application of the trend marker concept
would be ideal for the subjects having family history of the
disease in question or to the subjects who have got
pending undiagnosed disease conditions and who are
being treated for symptoms rather than root cause of the
disease.
Trend markers
A disease marker can be defined as an efficient diagnostic
indication that a specific disease may develop. Post development of a disease, such a marker can assist in confirmation of
its diagnosis. It also helps to differentiate between identical
presentations of disease symptoms which is essential for an
appropriate treatment. A disease marker needs to be a characteristic, measurable and quantifiable biological parameter
that can be objectively measured and evaluated as an indicator of either a normal or pathogenic process or pharmacologic responses to a therapeutic intervention.19
In the current scenario of medicine, disease markers are
routinely used mainly for predicting and diagnosing a disease
as well as for post treatment follow-up of patients. These
straight applications of disease markers are possible when
there is a single marker in question for a distinct set of
symptoms and a unique disease. But, in practice there are
varied situations possible. (1) There could be a single marker
predicting more than one distinct set of clinical symptoms or
getting affected by more than one disease conditions or (2)
there could be multiple parameters indicative of a particular
disease condition or (3) there is a possibility of multiple parameters resulting in several different presentations of the
same disease or (4) there could be a particular trend of a single
parameter or multiple parameters that could be predictive or
diagnostic of a disease or syndrome. For such complexities a
onetime measurement of the disease markers may not always
be sufficient to predict or diagnose or provide therapeutic
guidance. For such situations it would be right to introduce the
concept of “Trend Markers”. A trend marker can either be a
single marker or a group of individual markers which need to
be studied for individual diseases or group of diseases or
syndromes. Menstrual disease conditions are the model illustrations indicating the need for trend markers. There is a
need for studying trend in hormone levels with respect to the
disease conditions as demanded by the complexity and variety of symptoms. Menstrual diseases are ideal examples
where despite of the established hormonal graphics for the
three phases of menstrual cycle. In Fig. 120 the basal body
Conflicts of interest
The author has none to declare.
Acknowledgments
Fig. 1 e Menstrual cycle and hormones.
Special thanks to Dr. Atmaram Bandivdekar, National Institute of Research in Reproductive Health, Mumbai, India;

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a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 8 0 e2 8 4
Dr. Roby Russell, Roby Institute, Austin, TX, USA, Dr. Richard
Richardson and Dr. Patricia Richardson, University of Texas at
Austin, TX, USA, Dr. Gerhard Meisenberg, Ross University
School of Medicine, Roseau, Dominica, and Dr. William Simmons, Loyola University Stritch School of Medicine, Chicago,
IL, USA.
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