IJG-08439; No of Pages 4 International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
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International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
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CLINICAL ARTICLE
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Amr M.S. Abdel Hamid a,b,⁎, Tamer F. Borg a, Wael A.I. Madkour a,c
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Article history: Received 30 January 2015 Received in revised form 18 May 2015 Accepted 12 August 2015
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Keywords: Abnormal uterine bleeding Hyperprolactinemia Intermenstrual bleeding Menstruation Thyroid
Department of Obstetrics and Gynecology, Ain Shams University Hospital, Cairo, Egypt Department of Obstetrics and Gynecology, Hendawy Medical Center, Abu Dhabi, United Arab Emirates Dubai Fertility and Gynecology Center, Dubai, United Arab Emirates
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Objective: To evaluate the prevalence of hyperprolactinemia and thyroid disorders among patients with abnormal uterine bleeding (AUB) compared with matched controls. Methods: In 2013–2014, an observational study of women with AUB (group A) and women with regular menstruation (group B) was undertaken at one center in Egypt and one in the United Arab Emirates. Eligible women were aged 20–35 years and were not obese. Participants underwent clinical examinations, vaginal ultrasonography, office hysteroscopy (in selected cases), and measurement of hormone levels. Results: Hyperprolactinemia was present in 17 (16.2%) of 105 patients in group A and 4 (3.2%) of 125 patients in group B (P = 0.009). In group A, a high thyroid-stimulating hormone (TSH) level was observed in 8 (7.6%) patients and low levels of free triiodothyronine/thyroxine were found in 5 (4.8%) patients, compared with 2 (1.6%) patients and 1 (0.8%) patient in group B (P = 0.012 and P = 0.008, respectively). Polymenorrhea was the most frequent presentation of AUB (n = 60 [57.1%]). Five (29.4%) patients with hyperprolactinemia had galactorrhea. In group A, 8 (47.1%) patients with a high TSH had hyperprolactinemia, whereas 1 (1.1%) patient with a high TSH had a normal prolactin value (P = 0.008). Conclusion: Screening by evaluating prolactin and thyroid hormone levels is recommended for all patients with AUB, even in the absence of galactorrhea. © 2015 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics.
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1. Introduction
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Abnormal uterine bleeding (AUB) occurs in 9%–14% of women between menarche and menopause; the condition has a considerable quality-of-life and financial implications [1]. AUB is the complaint in approximately one-third of all gynecology consultations [2]. Hyperprolactinemia is a condition of elevated serum levels of prolactin, a 198-amino-acid protein (23 kD) produced in the lactotroph cells of the anterior pituitary gland [3]. In many cases of AUB, after ruling out various causes such as cervical or uterine pathology, or pregnancy, patients are usually managed by hormonal treatment or blind surgical therapy [4]. The prevalence of hyperprolactinemia varies from 0.4% in the normal adult population to as high as 9%–17% among women with menstrual conditions such as amenorrhea or polycystic ovarian syndrome [5,6]. A high serum prolactin level can disturb follicular maturation and corpus luteum function [7], and leads to inhibition of the normal pulsatile secretion of gonadotropin-releasing hormone in
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Prevalence of hyperprolactinemia and thyroid disorders among patients with abnormal uterine bleeding
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⁎ Corresponding author at: Hendawy Medical Center, 105521, Morour St, Abu Dhabi, United Arab Emirates. Tel.: +971 2 6213666; fax: +971 2 62137383. E-mail address:
[email protected] (A.M.S. Abdel Hamid).
the hypothalamus. It also provokes deficient secretion of luteinizing hormone and follicle-stimulating hormone, in amounts not adequate to induce a proper ovarian response [8]. Thyroid disorders are common in the female population, with approximately 0.8 per 1000 women per year developing hyperthyroidism and 3.5 per 1000 per year developing spontaneous hypothyroidism [9]. Thyroid hormones are thought to affect the menstrual pattern directly through an effect on ovarian-specific thyroid hormone receptors [10] and indirectly via their effects on sex hormone binding globulin, prolactin, and gonadotropin-releasing hormone secretion, and on coagulation factors [11]. Although National Institute for Health and Care Excellence guidelines [12] do not recommend the routine performance of thyroid function tests in women with menorrhagia, several studies [2,13] have shown that 15%–26% of menstrual cycle disorders result from thyroid dysfunction. Moragianni et al. [14] also highlighted the importance of thyroid function tests in patients with menorrhagia and concluded that medical treatment given in an appropriate timeframe can resolve the symptoms and preserve fertility potential. Although hyperprolactinemia and thyroid disorders are well-known causes of oligomenorrhea and amenorrhea, there is no consensus on whether screening for these disorders is recommended in patients with menstrual irregularities. Therefore, the present study was conducted to
http://dx.doi.org/10.1016/j.ijgo.2015.05.035 0020-7292/© 2015 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics.
Please cite this article as: Abdel Hamid AMS, et al, Prevalence of hyperprolactinemia and thyroid disorders among patients with abnormal uterine bleeding, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.05.035
54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75
100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138
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84 85
P value
t1:3
Age, y BMIb Parity Ethnic origin White Asian African
27.8 ± 0.1 24.5 ± 0.0 0–2
28.9 ± 0.0 26.8 ± 0.0 0–3
0.742 0.190 0.256
85 (81.0) 15 (14.3) 5 (4.8)
94 (75.2) 25 (20.0) 6 (4.8)
0.134 0.095 0.879
t1:4 t1:5 t1:6 t1:7 t1:8 t1:9 t1:10
Abbreviations: AUB, abnormal uterine bleeding; BMI, body mass index. a Values are given as mean ± SD, range, or number (percentage). b Calculated as weight in kilograms divided by the square of height in meters.
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The present cross-sectional, observational study was conducted from September 1, 2013, to September 30, 2014. Patients attending the outpatient gynecology and infertility clinics at Ain Shams University (Cairo, Egypt) or the Hendawy Medical Center (Abu Dhabi, United Arab Emirates) were recruited. Eligible women were aged 20–35 years and had a body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters) of less than 30. Group A included consecutive patients attending the clinics who had AUB in the form of menorrhagia (bleeding for 7 days or more with the same heaviness throughout, as stated by the patient), polymenorrhea (frequent cycles of fewer than 21 days), intermenstrual bleeding, or mixed patterns. Group B comprised age- and BMI-matched healthy women with regular menstruation, recruited from couples presenting with male factor infertility. The exclusion criteria for group A were: other forms of AUB (oligomenorrhea, primary or secondary amenorrhea); endocrine disorders leading to AUB, such as adrenal disorder and polycystic ovarian disease; organic causes of AUB, such as fibroids, polyps, or ovarian cysts; and hormonal treatment or treatment with medications that might have an impact on the menstrual flow or prolactin level, such as anticolitic treatment. Patients with suspected malignancy were also excluded, as were pregnant women, patients with a coagulation disorder, and those taking anticoagulation therapy. The exclusion criteria for group B were similar to those for group A; in addition, other causes of female factor infertility were excluded. The local medical ethics committees in both clinics granted approval for the study design and all participants provided informed consent. All participants underwent the following investigations to detect the presence of any organic pathology: medical history, history of drug intake, general examination, neck examination, examination for hyperandrogenic manifestations, determination of weight and BMI, breast examination for galactorrhea (performed after the determination of serum prolactin), and vaginal speculum examination. Subsequently, all patients were assessed by vaginal ultrasonography (Accuvix V10; Samsung Medison, Seoul, South Korea), which was performed by one sonographer in each department. In addition, the following hormone levels were assessed on days 1–3 of menstruation: luteinizing hormone and follicle-stimulating hormone (measured by radioimmunoassay; DIAsource ImmunoAssays, Nivelles, Belgium); prolactin (measured by radioimmunoassay; Siemens Healthcare Diagnostics Products, Marburg, Germany); thyroid-stimulating hormone (TSH) (measured by enzyme immunoassay; BioCheck, Foster City, CA, USA); and free triiodothyronine (T3) and free thyroxine (T4) (measured by enzyme-linked immunosorbent assay; BioCheck, Foster City, CA, USA). If a uterine lesion was suspected, hysterosonography or diagnostic hysteroscopy was performed. Sampling was done with the precautions described by Orija et al. [15]. Hyperprolactinemia was defined as a prolactin level of more than 1.13 nmol/L. An abnormal TSH level was defined as a value outside the range of 0.5–5.5 IU/L. Abnormal T3 and T4 levels were defined as values outside the ranges of 3.5–6.5 pmol/L and 10–23 pmol/L, respectively. A power calculation was performed to determine the required sample size, with a power of 80% and a confidence level of 95%. At least 100 patients needed to be recruited in each group. The data were analyzed using SPSS version 13 (SPSS Inc, Chicago, IL, USA). The χ2 test was used to compare categorical data. P b 0.05 was considered statistically significant.
Regular menstruation (n = 125)
3. Results
t1:11 t1:12 t1:13
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AUB (n = 105)
The present study included 105 patients presenting with AUB and 125 controls who were recruited from the infertility clinic. There were no significant differences between the groups in terms of age, BMI, parity, and ethnic origin (Table 1). The frequency of elevated prolactin levels was significantly higher in group A than in group B (16.2% vs 3.2%), and the mean prolactin level also differed considerably between the groups (Table 2). Moreover, elevated TSH levels were significantly more common in group A than in group B (7.6% vs 1.6%), and low levels of free T3 and T4 were also present in more patients in group A than in group B (4.8% vs 0.8%). By contrast, the frequencies of a low TSH level and elevated free T3/T4 levels did not differ significantly between the groups. Polymenorrhea was the most frequent type of AUB, affecting 60 (57.1%) patients (Table 3). Hyperprolactinemia was recorded in 10 (16.7%) of these patients, and an elevated TSH level was present in 5 (8.3%). A subanalysis including only group A revealed that galactorrhea was significantly more common among women with hyperprolactinemia than among those without hyperprolactinemia (P = 0.76) (Table 4). In another subanalysis involving only group A, an elevated level of TSH was significantly more common among patients with AUB who had hyperprolactinemia than among those who had a normal prolactin level (Table 5).
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4. Discussion
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The present study evaluated the prevalence of hyperprolactinemia and thyroid disorders among patients with AUB (excluding women with oligo-/amenorrhea), as compared with asymptomatic controls. A higher prevalence of hyperprolactinemia was identified among patients
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Table 2 Prolactin and thyroid hormone levels among women with and without AUB.a
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2. Materials and methods
Parameter
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78 79
t1:1 t1:2
Table 1 Demographic and obstetric characteristics of the study participants.a
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measure the prolactin and thyroid hormone levels among patients presenting with an abnormal menstrual pattern (defined as any change in the duration, amount, or frequency of menstrual flow, excluding oligoand amenorrhea), and to compare these levels with those in patients with regular menstruation to evaluate the usefulness of screening.
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Endocrine disorder
Hyperprolactinemia High prolactin (N1.13 nmol/l) Prolactin, ng/mL Hypothyroidism High TSH (N5.5 IU/L) TSH, IU/L Low free T3 and T4 Hyperthyroidism Low TSH (b0.5 IU/L) TSH, IU/L High free T3 and T4
141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161
165 166
AUB (n = 105)
Regular menstruation (n = 125)
P value
t2:3
17 (16.2) 29.5 ± 16.7 (7.4–67.4)
4 (3.2) 11.7 ± 6.9 (1.9–31.2)
0.009 0.010
t2:4 t2:5 t2:6
8 (7.6) 3.4 ± 3.0 (0.3–16.3) 5 (4.8)
2 (1.6) 2.4 ± 0.9 (1.3–6.3) 1 (0.8)
0.012 0.025
t2:7 t2:8 t2:9
1 (0.9) 2.6 ± 1.3 (1.5–5.4) 1 (1.0)
1 (0.8) 2.1 ± 1.0 (0.4–4.1) 1 (0.8)
0.950 0.086
t2:10 t2:11 t2:12 t2:13
0.950
t2:14
0.008
Abbreviations: AUB, abnormal uterine bleeding; T3, triiodothyronine; T4, thyroxine; TSH, t2:15 thyroid-stimulating hormone. t2:16 a Values are given as number (percentage) or mean ± SD (range). t2:17
Please cite this article as: Abdel Hamid AMS, et al, Prevalence of hyperprolactinemia and thyroid disorders among patients with abnormal uterine bleeding, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.05.035
A.M.S. Abdel Hamid et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
0.51 0.09 0.72
Abbreviations: AUB, abnormal uterine bleeding; PRL, prolactin; TSH, thyroid-stimulating hormone. a Values are given as number (percentage).
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with AUB, accompanied by a higher prevalence of hypothyroidism as indicated by an elevated TSH level and decreased levels of free T3/T4. These findings encouraged the study centers to implement screening for abnormal prolactin and thyroid hormone levels in all women of reproductive age who have AUB. By contrast, an elevated prolactin level occurred in only 3.2% of the women with normal menses; in most of these women, this elevation was very mild but persistent, which we believe does not mandate universal screening. Previous studies have evaluated the prevalence of hyperprolactinemia among patients with menstruation-related problems; most of these studies included patients with oligomenorrhea or amenorrhea. For example, Lee et al. [16] studied hyperprolactinemia in adolescents and young women with menstrual problems. They divided the study population in two groups based on age and found a 9.4% prevalence of hyperprolactinemia in the group aged 21–30 years compared with a 2.4% prevalence in the group aged 11–20 years. In other studies, the prevalence of hyperprolactinemia varied from approximately 0.2% in an unselected normal adult population to 15%–20% among women with reproductive disorders [17,18], whereas a study of women with a wider age range (15–45 years) [4] found that 61% of patients with abnormal bleeding had hyperprolactinemia. Some gynecologists will evaluate prolactin levels only in patients presenting with galactorrhea or in those with the classic picture of galactorrhea associated with oligomenorrhea or amenorrhea. In the current study, galactorrhea was present in 12.3% of the patients with AUB overall, but only 29.4% of those with an elevated prolactin level and abnormal menses had galactorrhea. This observation confirms a previous finding that galactorrhea was present in 30–80% of patients with a high serum prolactin level [19]. Thus, if prolactin levels are only measured in patients with galactorrhea, hyperprolactinemia will be missed in a considerable number of patients. One of the potential reasons for the absence of galactorrhea in some patients with elevated prolactin levels is the presence of estrogen deficiency, which causes an abnormal response to prolactin [6]. The presence of different molecular forms of prolactin, such as big prolactin and big big prolactin, which are not routinely tested for in laboratories, could also explain the detection of a normal prolactin level in the presence of galactorrhea. Nevertheless, in a study of 119 patients with an anovulatory cycle [20], 9% had hyperprolactinemia without galactorrhea, with an overall frequency of hyperprolactinemia of 15% in this study population. According to population estimates by the United States Census Bureau [21], 3.4% of the population have a thyroid disorder in the geographic area where the present study was conducted. The bulk of the literature reports an abnormal menstrual pattern in women with a thyroid disorder [12,22]. The observation of T3 receptors and TSH in the ovaries indicates a direct effect of T3 and TSH on steroidogenesis
182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212
t4:1 t4:2 t4:3
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Table 4 Prevalence of galactorrhea among patients with abnormal uterine bleeding by presence of hyperprolactinemia (n = 105).a
t4:4
Presence of hyperprolactinemia
Galactorrhea
P value
t4:5 t4:6
Yes (n = 17) No (n = 88)
5 (29.4) 8 (9.1)
0.076
t4:7
a
Values are given as number (percentage).
TSH level
Elevated prolactin (n = 17)
Normal prolactin (n = 88)
P value
t5:4
High (N5.5 IU/L) Low (b0.5 IU/L)
7 (41.2) 1 (5.9)
1 (1.1) 0
0.008 b0.001
t5:5 t5:6
Abbreviation: TSH, thyroid-stimulating hormone. a Values are given as number (percentage).
t5:7 t5:8
as well as a direct effect of estrogen on the secretion of thyroid hormones [10]. The present study showed a significant increase in the frequency of thyroid disorders among women with abnormal menses. Similarly, Attia et al. [23] reported significantly increased values of total and free T3/T4 among women with menorrhagia compared with controls. In a study of 135 women with menstrual irregularities (oligomenorrhea or amenorrhea) [13], 26% had an abnormal TSH level. It has been suggested that the treatment of thyroid dysfunction can reverse menstrual abnormalities and preserve a patient’s fertility potential [11,14], and some investigators have concluded that it is worth screening for a thyroid disorder in any woman with abnormal menses [6]. The National Institute for Health and Care Excellence guidelines for the management of AUB [12] recommend against the routine measurement of thyroid hormones and prolactin based on economic considerations, whereas a review from the American Academy of Family Physicians [24] recommends the measurement of both prolactin and TSH in patients with AUB. The association between thyroid disturbances and hyperprolactinemia has long been postulated, although some studies [25] have not find any correlation between prolactin and thyroid hormones. In people, TSH and prolactin secretion is controlled by an interrelated pathway. If a common regulatory mechanism is involved, the pituitary thyrotrophs and lactotrophs have shown differential sensitivity to the common stimulatory and inhibitory substances [26]. In the current study, the association between elevated prolactin levels and abnormal TSH was evident, indicating that the menstrual cycle is affected via a common pathway. The strengths of the current study are the use of clearly defined inclusion and exclusion criteria and its performance in two different countries with comparable patients, making the results reproducible. The present study is limited by the fact that not all possible thyroid function tests were applied, and measurement of different types of prolactin was not performed either; this did not seem relevant to clinical practice. The authors were aware of the new PALM-COEIN (polyp; adenomyosis; leiomyoma; malignancy and hyperplasia; coagulopathy; ovulatory dysfunction; endometrial; iatrogenic; and not yet classified) classification for AUB by the International Federation of Gynecology and Obstetrics, but the use of this classification system did not seem feasible in the present trial because the exact pathology of AUB in women with abnormal prolactin or thyroid hormone levels was unclear, and these patients might therefore fall under more than one category described in the new classification system. In conclusion, from a medical point of view it can be recommended to evaluate the levels of prolactin and thyroid hormones in women aged 20–35 years who present with an abnormal bleeding pattern, even in the absence of galactorrhea or thyroid manifestations, because this could help to identify the possible etiology of AUB and thus the best treatment approach. The financial implications of screening for prolactin/thyroid hormone abnormalities will have to be evaluated before a general recommendation can be made.
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Conflict of interests
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P value
5 (8.3) 2 (6.5) 1 (7.1)
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Elevated TSH
10 (16.7) 5 (16.1) 2 (14.3)
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Elevated PRL
Polymenorrhea (n = 60) Menorrhagia (n = 31) Intermenstrual bleeding (n = 14)
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Type of AUB
t3:4 t3:5 t3:6
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t3:3
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Table 5 t5:1 Association between hyperprolactinemia and an abnormal TSH level among patients with t5:2 abnormal uterine bleeding (n = 105).a t5:3
Table 3 Prevalence of hyperprolactinemia and elevated TSH by type of AUB (n = 105).a
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t3:1 t3:2
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The authors have no conflicts of interest.
Please cite this article as: Abdel Hamid AMS, et al, Prevalence of hyperprolactinemia and thyroid disorders among patients with abnormal uterine bleeding, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.05.035
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Please cite this article as: Abdel Hamid AMS, et al, Prevalence of hyperprolactinemia and thyroid disorders among patients with abnormal uterine bleeding, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.05.035
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