Concept of trend markers for menstrual diseases


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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.

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Concept of trend markers for menstrual diseases

  1. 1. Concept of trend markers for menstrual diseases.
  2. 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 ScienceDirect journal homepage: 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: 0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
  3. 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
  4. 4. 282 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 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
  5. 5. 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 4 283 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;
  6. 6. 284 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. references 1. Popat VB, Prodanov T, Calis KA, Nelson LM. The menstrual cycle a biological marker of general health in adolescents. Ann N Y Acad Sci. 2008;1135:43e51. 2. Bitzer J, Tschudin S, Stadlmayr W. Menstruation and its impact on women’s health [Article in German] Zentralbl Gynakol. 2005;127(5):282e287. 3. O’Flynn N, Britten N. Menorrhagia in general practice d disease or illness. Soc Sci Med. 2000;50:651e661. 4. Marshall J. An exploration of women’s concerns about heavy menstrual blood loss and their expectations regarding treatment. J Reprod Infant Psychol. 1998;16:259e276. 5. Master-Hunter Tarannum, Heiman DL. Amenorrhea: evaluation and treatment. Am Fam Physician. 2006;73(8):1374e1382. 6. Wyatt K, Dimmock PW, O’Brien PM. Premenstrual syndrome. In: Barton S, ed. Clinical Evidence. London: BMJ Publishing Group; 2000:1121e1133, 4th issue. 7. Steiner M, Born L. Diagnosis and treatment of premenstrual dysphoric disorder: an update. Int Clin Psychopharmacol. 2000;15(suppl 3):S5eS17. 8. Kessel B. Premenstrual syndrome. Advances in diagnosis and treatment. Obstet Gynecol Clin North Am. 2000;27:625e639. 9. Skobeloff EM, Spivey WH, St. Clair SS, Schoffstall JM. The influence of age and sex on asthma admissions. JAMA. 1992;268:3437e3440. 10. Granella F, Sances G, Allais G, et al. Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centres. Cephalalgia. 2004;24(9):707e716. 11. MacGregor EA. Oestrogen and attacks of migraine with and without aura. Lancet Neurol. 2004;3:354e361. 12. MacGregor EA, Hackshaw A. Prevalence of migraine on each day of the natural menstrual cycle. Neurology. 2004;63:351e353. 13. Martin VT, Wernke S, Mandell K, Grumbach MM. Defining the relationship between ovarian hormones and migraine headache. Headache. 2005;45:1190e1201. 14. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders. 2nd ed. Cephalalgia. 2004;24(1):138e149. 15. Karlson Elizabeth W, Mandl Lisa A, Hankinson Susan E, Grodstein Francine. Do breast-feeding and other reproductive factors influence future risk of rheumatoid arthritis? Results from the nurses’ health study. Arthritis Rheum. Nov 2004;50(11):3458e3467. 16. Laufer MR, Floor AE, Parsons KE, Kuntz KM, Barbieri RL. Hormone testing in women with adult-onset amenorrhea. Gynecol Obstet Invest. 1995;40(3):200e203. 17. Chapple A, May C, Ling M. Is objective testing for menorrhagia in general practice practical? Results from a qualitative study. Eur J Gen Pract. 2001;7:13e17. 18. O’Flynn Norma, Britten Nicky. Diagnosing menstrual disorders: a qualitative study of the approach of primary care professionals. Br J Gen Pract. 2004;54(502):353e358. 19. Strimbu Kyle, Tavel Jorge A. What are biomarkers? Curr Opin HIV AIDS. 2010;5(6):463e466. 20. Silverthorn Dee Unglaub. Human Physiology: An Integrated Approach. 6th ed. Glenview, IL: Pearson Education, Inc; 2013:850e890.
  7. 7. A o oh s i l ht:w wa o o o p a . m/ p l o p a : t / w .p l h s i lc l ts p / l ts o T ie: t s / ie. m/o p a A o o wt rht :t t r o H s i l p l t p /w t c ts l Y uu e ht:w wy uu ec m/p l h s i ln i o tb : t / w . tb . a o o o p a i a p/ o o l ts d F c b o : t :w wfc b o . m/h A o o o p a a e o k ht / w . e o k o T e p l H s i l p/ a c l ts Si s ae ht:w wsd s aen t p l _ o p a l e h r: t / w .i h r.e/ o o H s i l d p/ le A l ts L k d : t :w wl k d . m/ mp n /p l -o p a i e i ht / w . e i c c a y o oh s i l n n p/ i n no o a l ts Bo : t :w wl s l e l . / l ht / w . t a h a hi g p/ e tk t n