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Increased incidence of pelvic organ prolapse in women with acromegaly
European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 44–47
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Increased incidence of pelvic organ prolapse in women with acromegaly Ozlem Celik a, Suleyman Engin Akhan b, Esra Hatipoglu a, Pinar Kadioglu a,* a b
Division of Endocrinology and Metabolism, Department of Internal Medicine, Cerrahpasa Medical School, University of Istanbul, Istanbul, Turkey Department of Gynecology and Obstetrics, Istanbul Medical School, University of Istanbul, Istanbul, Turkey
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 July 2014 Received in revised form 22 September 2014 Accepted 4 October 2014
Objective: To evaluate gynecological problems of female patients with acromegaly and the relationship of these problems with the activity of the disease. Study design: Thirty-four women with acromegaly and 27 age- and body mass index-matched female healthy controls (HC) were included in the study. Demographic features, medical history, hormonal status and disease activity were obtained. A detailed gynecological examination was performed. Results: The incidence of pelvic organ prolapse (POP) was higher in patients with acromegaly (53%, n = 18) compared to the HC (15%, n = 4) (p = 0.003). Limiting the analysis to only cases with previous pregnancy, POP was seen in 18 (60%) of 30 cases with acromegaly and in 4 (20%) of 20 of the HC (p = 0.005). Additionally, in cases with prior vaginal delivery, POP was present in 18 (60%) of 30 cases with acromegaly and in 4 (24%) of 17 of the HC (p = 0.02). The frequency of POP was similar in patients with controlled and uncontrolled acromegaly (p = 0.3). Conclusion: Acromegaly may facilitate occurrence of pelvic organ prolapse and may cause additional health issues in female cases. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Acromegaly Fertility Gynecological problems Pregnancy Pelvic organ prolapse
Introduction Acromegaly is a state of excessive GH secretion, usually caused by a benign pituitary adenoma. In addition to its endocrine and metabolic consequences, it also has effects on various organs and tissues [1–4]. Previous reports have concluded that GH and IGF-1 receptors are widely expressed in many cells, including the gonads and genitalia [5–8]. It is therefore plausible that excessive GH or IGF-1 may also affect pelvic organs and may cause gynecologic problems in female patients with acromegaly. Because acromegaly is a rare disease with an insidious onset and usually diagnosed at midlife, few data are available on the frequency and causes of gynecological problems. The aim of this study was to evaluate gynecological problems of female patients with acromegaly and the relationship of these problems with disease activity. Methods A total of 34 women with acromegaly (controlled/uncontrolled:14/20), who were followed up and treated at the
* Corresponding author. Tel.: +90 5324041040; fax: +90 212 2333806. E-mail address: [email protected] (P. Kadioglu). http://dx.doi.org/10.1016/j.ejogrb.2014.10.009 0301-2115/ß 2014 Elsevier Ireland Ltd. All rights reserved.
Cerrahpasa Medical School Endocrinology and Metabolism Outpatient Clinic between 1990 and 2013, were included in the study. A total of 27 age- and body mass index (BMI)-matched healthy female subjects without a chronic or endocrine disease comprised the healthy controls (HC). Demographic characteristics and medical history were obtained from all subjects. Cases who had had radiotherapy (RT) for control of acromegaly were asked about the order in which RT and pregnancy occurred. Fourteen cases with acromegaly (controlled: 8, uncontrolled: 6) and 10 of the HC had entered the menopause. A detailed gynecological examination was performed by the same gynecologist (S.E.A). Controlled disease activity was determined by the presence of clinical findings and failure to suppress the nadir GH level to less than 1 ng/mL during an oral glucose tolerance test (OGTT) and as well as high levels of IGF-1 adjusted for age and gender [9]. All the parameters were evaluated according to disease activity and compared to HC. Blood samples were taken to determine the levels of hormones before 10am in the early follicular phase in premenopausal and on any day in postmenopausal cases. A chemiluminescence immunoassay was done to assess PRL (normal: 3–23.3 ng/mL), LH (normal: 2.4–12.6 mIU/mL), FSH (normal: 3.6–12.5 mIU/mL), estradiol (normal: 12.5–166 pg/mL), DHEA-SO4 (normal: 96–340 mg/dL), total testosterone (normal: 0.05–0.82 ng/mL), cortisol (normal:
O. Celik et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 44–47
6.2–19.4 mg/dL), TSH (normal: 0.4–4.0 mIU/mL), and free thyroxine (normal: 0.8–1.9 ng/dL). A radioimmunoassay was done to assess free testosterone (normal: 0.45–3.17 pg/mL), 17-OH progesterone (normal: 0.15–1.3 ng/mL) and androstenedione (normal: 0.1–2.9 ng/mL). IGF-1 levels were evaluated after ethanol extraction with IRMA (Diagnostic System Laboratories Inc. Webster, Texas U.S.A.; normal values: 100–494 ng/mL for ages of 30–40 years, 101–303 ng/mL for ages of 40–50 years, and 78–258 ng/mL for ages of 50–70 years). Plasma GH levels were also studied with IRMA (GH; Immunotech, Marseille, France; normal value <10 ng/mL). Insulin resistance (IR) was calculated by homeostasis model of assessment (HOMA). Cases with HOMAIR >2.5 were considered to have insulin resistance [10]. The study protocol was approved by the Ethics Committee of Cerrahpasa Medical School, Istanbul University. All the subjects read and signed the informed consent forms before enrolling in the study. The data were statistically analyzed using the SPSS 15.0 package program. The chi-square test was used for categorical variables. The Mann–Whitney U test was used to compare independent variables. Spearman’s correlation coefficient was used for the calculation of associations between variables. p < 0.05 was considered statistically significant. Results The mean age of the patients with acromegaly was 46.2 10.8 years and of the control group was 43.3 12.7 years (p = 0.3). The mean BMIs of patients with acromegaly and of the HC were 31.9 6.8 and 30.6 6.5 kg/m2, respectively (p = 0.5). There was no difference between the patients and the HC in terms of income level, smoking habits, menopausal status, and the time elapsed since entering menopause (p = 0.1, p = 0.7, p = 0.7 and p = 0.7, respectively). The acromegalic patients had lower levels of education, were more likely to be of rural origin, and had greater prevalence of Table 1 Demographic data of the female patients with acromegaly and healthy controls. Acromegaly (n, %)
Healthy controls (n, %)
0.01*
Origin Rural Urban
26 (76.5) 8 (23.5)
12 (44) 15 (56)
Educational level Low education (?8 years) High education (>8 years)
29 (85) 5 (15)
10 (37) 17 (63)
Income level ($/month) <500 500–<1000 1000–2500 >2500
12 16 6 0
6 12 5 4
Smoking history Present Absent
4 (12) 30 (88)
Associated complications Hypertension Diabetes mellitus Sleep apnea syndrome Hypopituitarism
18 14 8 7
Menstruation status Menstrual cycle (+) Menopause
20 (59) 14 (41)
Menopause duration (months) *
statistically significant p values.
p
<0.001*
0.1 (35) (47) (18) (0)
(53) (41) (24) (21)
(22) (44) (19) (15)
0.7 4 (15) 23 (85)
1 1 0 0
(4) (4) (0) (0)
<0.001* 0.001* 0.007* 0.01* 0.7
112.3 61.8
17 (63) 10 (37) 125.5 92
0.7
45
diabetes mellitus (DM), hypertension, and obstructive sleep apnea syndrome (OSAS) compared to HC (p < 0.001, p = 0.01, p = 0.001, p < 0.001 and p = 0.007, respectively). The demographic data of the groups are shown in Table 1. The mean duration of the disease was 156 [IQR = 48–186] months in controlled acromegaly patients and 42 months [IQR = 25–1114] in uncontrolled patients (p < 0.01). A history of transsphenoidal surgery was present in 12 (86%) cases with controlled and 18 (90%) cases with uncontrolled acromegaly (p = 0.7). Seven of the controlled acromegaly cases and 6 of the uncontrolled cases had a history of RT (p = 0.007). Twelve of the controlled cases and 14 of the uncontrolled cases had received medical treatment (p = 0.3). Of the cases with controlled acromegaly seven (50%) were on somatostatin analog (SSA) and five (36%) were on SSA + dopamine agonist (DA). Of the cases with uncontrolled acromegaly, four (20%) were on SSA, one (5%) was on DA, six (30%) were on SSA + DA, two (10%) were on SSA + Pegvisomant (PEG) and one (5%) was on SSA + DA + PEG. Four patients (29%) with controlled and three patients (15%) with uncontrolled acromegaly had hypopituitarism. Two patients had hypothyroidism and hypogonadism, two had hypocortisolism and hypogonadism, one had hypogonadism, and two had hypocortisolism. They were receiving appropriate hormone replacement therapy. DHEA-SO4, total testosterone and cortisol levels were lower in cases with acromegaly (p = 0.003, p = 0.04 and p = 0.002, respectively). The median basal serum levels of FSH, LH, estradiol and HOMA-IR did not differ significantly among the groups (Table 2). Acromegaly cases with hypopituitarism had lower levels of DHEA-SO4, total testosterone and cortisol levels compared to cases without hypopituitarism (p = 0.01, p = 0.005 and p = 0.02, respectively). The total number of pregnancies was 116 (median: 4 [IQR: 2–5, min–max: 0–8]) in cases with acromegaly (controlled/uncontrolled: 49/67) and 55 (median: 2 [IQR: 1–3, min–max: 0–7]) in the HC (p = 0.01). The median number of parity was also higher, albeit rather insignificantly, in cases with acromegaly (2 [IQR: 2–4, min– max: 0–6]) compared to the HC (2 [IQR: 1–3, min–max: 0–4]) (p = 0.06) (Table 3). No difference was found in median number of previous pregnancies between controlled and uncontrolled acromegaly groups (4 [IQR: 2–5] and 3 [IQR: 2–5], respectively; p = 0.8). In all of the cases with acromegaly, pregnancies had occurred before RT. There was also no difference in the median number of parity between the controlled (3 [IQR: 2–4]) and uncontrolled (2 [IQR: 2–3]) cases of acromegaly (p = 0.5). Cases with acromegaly had a higher incidence of miscarriages compared to the HC (0 [IQR: 0–2, min–max: 0–3] and 0 [IQR: 0–0, min–max: 0–3], p = 0.02) (Table 3). There was no difference in the median number of miscarriages between the controlled (0 [IQR: 0–1]) and uncontrolled (0 [IQR: 0–2]) acromegaly groups (p = 0.7). The number of a miscarriages was positively correlated with number of pregnancies (r = 0.8, p < 0.001). A cervical polyp was detected in one case with acromegaly who had controlled disease activity, and in none of the HC (p = 0.4). The frequency of pelvic organ prolapse (POP) was significantly higher in patients with acromegaly than in the HC (p = 0.003). The frequency of POP was similar in controlled and uncontrolled acromegaly patients (p = 0.3). There was no difference in GH and IGF-1 levels between cases with and those without POP (p = 0.3 and p = 0.7, respectively). Moreover when only cases with POP were taken into consideration, numbers of total pregnancies, parity and miscarriages were not statistically different between cases with acromegaly and HC (p = 0.2, p = 0.3 and p = 0.5). Limiting the analysis to only cases of previous pregnancy, POP was seen in 18 (60%) of 30 cases with acromegaly and in 4 (20%) of
46
O. Celik et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 44–47
Table 2 HOMA-IR and hormone levels in female patients with acromegaly and healthy controls.
HOMA-IR Free T4 (ng/dL) TSH (mIU/L) Estradiol (pg/mL) FSH (mIU/mL) LH (mIU/mL) PRL (ng/mL) DHEA-SO4 (mcg/dL) Androstenedione (ng/mL) Total testosterone (ng/mL) Free testosterone (pg/mL) 17OH Progesterone (ng/mL) Cortisol (mcg/dL) GH (ng/mL) IGF-1 (ng/mL)
Acromegaly (n = 34)
Healthy controls (n = 27)
p
1.8 [0.7–3.5] 1.3 [1.2–1.4] 1.4 [0.8–2.1] 24.1 [8.6–38.5] 7.2 [4.9–30.3] 4.39 [2.3–16.5] 8.1 [0.7–15.2] 108 [71.9–142.8] 1 [0.8–1.5] 0.2 [0.1–0.2] 1 [0.7–1.3] 0.5 [0.4–0.7] 12 [9.6–15] 1.4 [0.9–2.9] 447 [328.8–749]
1.9 [0.6–3.6] 1.32 [1.17–1.36] 1.54 [1–1.95] 31.3 [19.7–52.3] 7.8 [6.1–58.9] 8.1 [5.1–25] 10.7 [8–16] 185 [129.7–252] 1.45 [0.84–1.69] 0.24 [0.18–0.31] 1.2 [0.83–1.68] 0.44 [0.35–0.53] 16 [12.8–19.1] 0.64 [0.18–1.21] 335.5 [264.5–393.3]
0.6 0.3 0.05 0.09 0.4 0.07 0.09 0.003* 0.1 0.04* 0.2 0.3 0.002* <0.001* <0.001*
Data are expressed as median and IQR. * statistically significant p values.
20 subjects in the HC (p = 0.005). Additionally, in cases with prior vaginal delivery, POP was present in 18 (60%) of 30 cases with acromegaly and in 4 (24%) of 17 of the subjects in the HC (p = 0.02). Comment In the current study, the frequencies of POP and miscarriage were greater in female cases with acromegaly. The majority of the other findings of gynecologic examination and history did not reveal an obvious difference between cases with and without acromegaly. Table 3 Findings of the gynecologic examination and history of the female patients with acromegaly and healthy controls. Acromegaly (n, %) TAHBSO Cervical polyp Myoma Menopausal findings Pelvic organ prolapse Rectocoele Cystocoele Uterine descent Combined Dysfunctional uterine bleeding Incontinence
3 1 2 12
(9%) (3%) (6%) (36%)
Healthy controls (n,%)
p
0 0 0 10
0.1 0.4 0.2 0.3
(0%) (0%) (0%) (37%)
18 (53%) 1 (6%) 7 (39%) 1 (6%) 9 (50%) 1 (3%) 4 (12%) (3 mixed type and 1urge type)
4 (15%) 3 (11%) 1 (4%) 0 (0%) 0 (0%) 0 (0%) 4 (15%) (1 mixed and 3 stress type)
116 4
55 2
Number of parity Total Median
88 2
47 2
Number of miscarriages Total Median
29 0
8 0
Mode of delivery Vaginal C/S Unknown
30 (88%) 1 (3%) 3 (9%)
Number of pregnancies Total Median
0.003**
0.4 0.7
0.01**
0.06
0.02**
0.07 17 (63%) 3 (11%) 7 (26%)
TAHBSO Total abdominal hysterectomy with bilateral salpingo-oophorectomy, C/S cesarean section. ** statistically significant p values.
POP is the descent of pelvic organs into the vaginal canal and occurs with advanced age and vaginal parity [11–13]. It is associated with pelvic floor dysfunction and constitutes a major health problem, especially for women above 50 years old [14]. Menopause, obesity and cigarette smoking constitute additional risk factors for POP [15–17]. Its prevalence varies between 25% and 97% of the population [18]. In this study, fewer HC had POP (4/27 (15%)) compared to what has previously been reported. The mean age of the two groups was less than 50 so this could explain why the frequency of POP was lower in our HC. Cases with acromegaly, however, had increased frequency of POP compared to the HC. Since mean age, BMI, menopausal status and smoking history were similar in the two groups, these risk factors were eliminated as sources of higher POP in cases with acromegaly. Increased numbers of pregnancies in cases with acromegaly could be responsible for POP; nevertheless, the numbers of parity and mode of deliveries were similar in the groups. Moreover in cases with POP the number of pregnancies, parity and miscarriages did not differ between cases with acromegaly and HC, meaning that the increased incidence of POP in acromegaly may not be related to the number of pregnancies, parity or miscarriages. Additionally, when all the subjects with prior pregnancy were taken into consideration, it was seen that the frequency of POP was still greater in acromegaly cases than in the HC. Similarly, among those with prior vaginal birth, women with acromegaly had a higher incidence of POP than in the HC. This means that, in addition to preexisting factors including previous pregnancy and vaginal parity, GH and/or IGF-1 excess could be also a risk factor for POP. There was no difference, however, in the occurrence of POP between the controlled and uncontrolled cases with acromegaly, so POP may be an irreversible outcome of excessive GH/IGF-1 secretion. Damage to the pelvic floor neuromusculature and connective tissue has been suggested as a causative factor of POP [19]. GH may alter the composition of the extracellular matrix and acromegaly is known to cause valvular and aortic root changes comparable with the connective tissue disease, Marfan’s syndrome [20,21]. Moreover, acromegaly has been linked with diverticular disease due to irreversible changes in the collagen of the colon [22]. It may therefore be speculated that in addition to the wellknown effects of GH and IGF-1 on various tissues, GH and IGF-1 may also weaken pelvic floor connective tissue. In the majority of cases in this series, pregnancies had occurred before diagnosis of acromegaly and RT, so our data are insufficient to draw a conclusion about the impact of acromegaly or RT on fertility. Nevertheless, it is interesting that there was a total of 116 pregnancies in 34 women with acromegaly, which is a strikingly
O. Celik et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 44–47
high incidence of pregnancy. In addition, cases with acromegaly had a higher number of pregnancies than the HC. This result could be partly explained by the socioeconomic differences between the groups, e.g., lower levels of education and being of rural origin, in cases with acromegaly. The number of pregnancies was negatively correlated with educational levels and positively correlated with rural origins (i.e., the lower the educational level, the greater the number of pregnancies. Similarly, women with rural origins were more likely to have higher number of pregnancies). Although cortisol, DHEA-SO4 and total testosterone levels were lower in acromegaly, their levels were not sufficiently low to have clinical significance. Hypopituitarism may have contributed to lower levels in the acromegaly group compared to HC. There was a greater number of miscarriages in cases with acromegaly than in the HC. This is not surprising when broad and possible effects of GH/IGF-1 excess are considered. This effect, however, may be an irreversible outcome of acromegaly since number of miscarriages did not differ according to disease activity and was not associated with GH or IGF-1. Moreover, the higher incidence of miscarriages may be associated with greater numbers of pregnancies, but the reason for miscarriage in the current cohort is unknown. The absolute prevalence of miscarriage in cases with acromegaly can be established by further studies involving increased numbers of cases. To our knowledge, this is the first controlled study evaluating gynecologic findings in female cases of acromegaly, specifically POP. Acromegaly may affect pelvic structures and facilitate the occurrence of pelvic organ prolapse, and may therefore cause additional health issues and reduce quality of life in female patients. Conflict of interest statement The authors declare no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported. Funding The study was supported by the Research Fund of the University of Istanbul. Istanbul, Turkey, Project No. 13244. Condensation Acromegaly causes additional health issues and reduces quality of life in female patients by affecting pelvic structures and facilitating the occurrence of pelvic organ prolapse.
47
References [1] Ben-Shlomo A, Melmed S. Acromegaly. Endocrinol Metab Clin North Am 2008;37:101–22 (viii). [2] Bondanelli M, Ambrosio MR, degli Uberti EC. Pathogenesis and prevalence of hypertension in acromegaly. Pituitary 2001;4:239–49. [3] Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev 2004;25: 102–52. [4] Fatti LM, Scacchi M, Pincelli AI, Lavezzi E, Cavagnini F. Prevalence and pathogenesis of sleep apnea and lung disease in acromegaly. Pituitary 2001;4: 259–62. [5] Kopchick JJ, Andry JM. Growth hormone (GH), GH receptor, and signal transduction. Mol Genet Metab 2000;71:293–314. [6] Lobie PE, Breipohl W, Aragon JG, Waters MJ. Cellular localization of the growth hormone receptor/binding protein in the male and female reproductive systems. Endocrinology 1990;126:2214–21. [7] Daftary SS, Gore AC. IGF-1 in the brain as a regulator of reproductive neuroendocrine function. Exp Biol Med (Maywood) 2005;230:292–306. [8] Hull KL, Harvey S. Growth hormone: a reproductive endocrine-paracrine regulator. Rev Reprod 2000;5:175–82. [9] Giustina A, Chanson P, Bronstein MD, et al. A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab 2010;95:3141–8. [10] Bastard JP, Grimaldi A, Jardel C, Porquet D, Bruckert E, Hainque B. A simple index of insulin resistance. Diabetes Metab 1997;23:87–8. [11] Hendrix SL, Clark A, Nygaard I, Aragaki A, Barnabei V, McTiernan A. Pelvic organ prolapse in the Women’s Health Initiative: gravity and gravidity. Am J Obstet Gynecol 2002;186:1160–6. [12] Swift SE. The distribution of pelvic organ support in a population of female subjects seen for routine gynecologic health care. Am J Obstet Gynecol 2000;183:277–85. [13] Awwad J, Sayegh R, Yeretzian J, Deeb ME. Prevalence, risk factors, and predictors of pelvic organ prolapse: a community-based study. Menopause 2012;19:1235–41. [14] Samuelsson EC, Victor FT, Tibblin G, Svardsudd KF. Signs of genital prolapse in a Swedish population of women 20 to 59 years of age and possible related factors. Am J Obstet Gynecol 1999;180:299–305. [15] Sze EH, Hobbs G. A prospective cohort study of pelvic support changes among nulliparous, multiparous, and pre- and post-menopausal women. Eur J Obstet Gynecol Reprod Biol 2012;160:232–5. [16] Gyhagen M, Bullarbo M, Nielsen TF, Milsom I. Prevalence and risk factors for pelvic organ prolapse 20 years after childbirth: a national cohort study in singleton primiparae after vaginal or caesarean delivery. BJOG 2013;120: 152–60. [17] Chow D, Rodriguez LV. Epidemiology and prevalence of pelvic organ prolapse. Curr Opin Urol 2013;23:293–8. [18] Nygaard I, Bradley C, Brandt D. Pelvic organ prolapse in older women: prevalence and risk factors. Obstet Gynecol 2004;104:489–97. [19] Dietz HP, Simpson JM. Levator trauma is associated with pelvic organ prolapse. BJOG 2008;115:979–84. [20] Thompson BJ, Shang CA, Waters MJ. Identification of genes induced by growth hormone in rat liver using cDNA arrays. Endocrinology 2000;141: 4321–4. [21] van der Klaauw AA, Bax JJ, Smit JW, et al. Increased aortic root diameters in patients with acromegaly. Eur J Endocrinol 2008;159:97–103. [22] Wassenaar MJ, Cazemier M, Biermasz NR, et al. Acromegaly is associated with an increased prevalence of colonic diverticula: a case-control study. J Clin Endocrinol Metab 2010;95:2073–9.
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Increased incidence of pelvic organ prolapse in women with acromegaly Ozlem Celik a, Suleyman Engin Akhan b, Esra Hatipoglu a, Pinar Kadioglu a,* a b
Division of Endocrinology and Metabolism, Department of Internal Medicine, Cerrahpasa Medical School, University of Istanbul, Istanbul, Turkey Department of Gynecology and Obstetrics, Istanbul Medical School, University of Istanbul, Istanbul, Turkey
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 July 2014 Received in revised form 22 September 2014 Accepted 4 October 2014
Objective: To evaluate gynecological problems of female patients with acromegaly and the relationship of these problems with the activity of the disease. Study design: Thirty-four women with acromegaly and 27 age- and body mass index-matched female healthy controls (HC) were included in the study. Demographic features, medical history, hormonal status and disease activity were obtained. A detailed gynecological examination was performed. Results: The incidence of pelvic organ prolapse (POP) was higher in patients with acromegaly (53%, n = 18) compared to the HC (15%, n = 4) (p = 0.003). Limiting the analysis to only cases with previous pregnancy, POP was seen in 18 (60%) of 30 cases with acromegaly and in 4 (20%) of 20 of the HC (p = 0.005). Additionally, in cases with prior vaginal delivery, POP was present in 18 (60%) of 30 cases with acromegaly and in 4 (24%) of 17 of the HC (p = 0.02). The frequency of POP was similar in patients with controlled and uncontrolled acromegaly (p = 0.3). Conclusion: Acromegaly may facilitate occurrence of pelvic organ prolapse and may cause additional health issues in female cases. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Acromegaly Fertility Gynecological problems Pregnancy Pelvic organ prolapse
Introduction Acromegaly is a state of excessive GH secretion, usually caused by a benign pituitary adenoma. In addition to its endocrine and metabolic consequences, it also has effects on various organs and tissues [1–4]. Previous reports have concluded that GH and IGF-1 receptors are widely expressed in many cells, including the gonads and genitalia [5–8]. It is therefore plausible that excessive GH or IGF-1 may also affect pelvic organs and may cause gynecologic problems in female patients with acromegaly. Because acromegaly is a rare disease with an insidious onset and usually diagnosed at midlife, few data are available on the frequency and causes of gynecological problems. The aim of this study was to evaluate gynecological problems of female patients with acromegaly and the relationship of these problems with disease activity. Methods A total of 34 women with acromegaly (controlled/uncontrolled:14/20), who were followed up and treated at the
* Corresponding author. Tel.: +90 5324041040; fax: +90 212 2333806. E-mail address: [email protected] (P. Kadioglu). http://dx.doi.org/10.1016/j.ejogrb.2014.10.009 0301-2115/ß 2014 Elsevier Ireland Ltd. All rights reserved.
Cerrahpasa Medical School Endocrinology and Metabolism Outpatient Clinic between 1990 and 2013, were included in the study. A total of 27 age- and body mass index (BMI)-matched healthy female subjects without a chronic or endocrine disease comprised the healthy controls (HC). Demographic characteristics and medical history were obtained from all subjects. Cases who had had radiotherapy (RT) for control of acromegaly were asked about the order in which RT and pregnancy occurred. Fourteen cases with acromegaly (controlled: 8, uncontrolled: 6) and 10 of the HC had entered the menopause. A detailed gynecological examination was performed by the same gynecologist (S.E.A). Controlled disease activity was determined by the presence of clinical findings and failure to suppress the nadir GH level to less than 1 ng/mL during an oral glucose tolerance test (OGTT) and as well as high levels of IGF-1 adjusted for age and gender [9]. All the parameters were evaluated according to disease activity and compared to HC. Blood samples were taken to determine the levels of hormones before 10am in the early follicular phase in premenopausal and on any day in postmenopausal cases. A chemiluminescence immunoassay was done to assess PRL (normal: 3–23.3 ng/mL), LH (normal: 2.4–12.6 mIU/mL), FSH (normal: 3.6–12.5 mIU/mL), estradiol (normal: 12.5–166 pg/mL), DHEA-SO4 (normal: 96–340 mg/dL), total testosterone (normal: 0.05–0.82 ng/mL), cortisol (normal:
O. Celik et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 44–47
6.2–19.4 mg/dL), TSH (normal: 0.4–4.0 mIU/mL), and free thyroxine (normal: 0.8–1.9 ng/dL). A radioimmunoassay was done to assess free testosterone (normal: 0.45–3.17 pg/mL), 17-OH progesterone (normal: 0.15–1.3 ng/mL) and androstenedione (normal: 0.1–2.9 ng/mL). IGF-1 levels were evaluated after ethanol extraction with IRMA (Diagnostic System Laboratories Inc. Webster, Texas U.S.A.; normal values: 100–494 ng/mL for ages of 30–40 years, 101–303 ng/mL for ages of 40–50 years, and 78–258 ng/mL for ages of 50–70 years). Plasma GH levels were also studied with IRMA (GH; Immunotech, Marseille, France; normal value <10 ng/mL). Insulin resistance (IR) was calculated by homeostasis model of assessment (HOMA). Cases with HOMAIR >2.5 were considered to have insulin resistance [10]. The study protocol was approved by the Ethics Committee of Cerrahpasa Medical School, Istanbul University. All the subjects read and signed the informed consent forms before enrolling in the study. The data were statistically analyzed using the SPSS 15.0 package program. The chi-square test was used for categorical variables. The Mann–Whitney U test was used to compare independent variables. Spearman’s correlation coefficient was used for the calculation of associations between variables. p < 0.05 was considered statistically significant. Results The mean age of the patients with acromegaly was 46.2 10.8 years and of the control group was 43.3 12.7 years (p = 0.3). The mean BMIs of patients with acromegaly and of the HC were 31.9 6.8 and 30.6 6.5 kg/m2, respectively (p = 0.5). There was no difference between the patients and the HC in terms of income level, smoking habits, menopausal status, and the time elapsed since entering menopause (p = 0.1, p = 0.7, p = 0.7 and p = 0.7, respectively). The acromegalic patients had lower levels of education, were more likely to be of rural origin, and had greater prevalence of Table 1 Demographic data of the female patients with acromegaly and healthy controls. Acromegaly (n, %)
Healthy controls (n, %)
0.01*
Origin Rural Urban
26 (76.5) 8 (23.5)
12 (44) 15 (56)
Educational level Low education (?8 years) High education (>8 years)
29 (85) 5 (15)
10 (37) 17 (63)
Income level ($/month) <500 500–<1000 1000–2500 >2500
12 16 6 0
6 12 5 4
Smoking history Present Absent
4 (12) 30 (88)
Associated complications Hypertension Diabetes mellitus Sleep apnea syndrome Hypopituitarism
18 14 8 7
Menstruation status Menstrual cycle (+) Menopause
20 (59) 14 (41)
Menopause duration (months) *
statistically significant p values.
p
<0.001*
0.1 (35) (47) (18) (0)
(53) (41) (24) (21)
(22) (44) (19) (15)
0.7 4 (15) 23 (85)
1 1 0 0
(4) (4) (0) (0)
<0.001* 0.001* 0.007* 0.01* 0.7
112.3 61.8
17 (63) 10 (37) 125.5 92
0.7
45
diabetes mellitus (DM), hypertension, and obstructive sleep apnea syndrome (OSAS) compared to HC (p < 0.001, p = 0.01, p = 0.001, p < 0.001 and p = 0.007, respectively). The demographic data of the groups are shown in Table 1. The mean duration of the disease was 156 [IQR = 48–186] months in controlled acromegaly patients and 42 months [IQR = 25–1114] in uncontrolled patients (p < 0.01). A history of transsphenoidal surgery was present in 12 (86%) cases with controlled and 18 (90%) cases with uncontrolled acromegaly (p = 0.7). Seven of the controlled acromegaly cases and 6 of the uncontrolled cases had a history of RT (p = 0.007). Twelve of the controlled cases and 14 of the uncontrolled cases had received medical treatment (p = 0.3). Of the cases with controlled acromegaly seven (50%) were on somatostatin analog (SSA) and five (36%) were on SSA + dopamine agonist (DA). Of the cases with uncontrolled acromegaly, four (20%) were on SSA, one (5%) was on DA, six (30%) were on SSA + DA, two (10%) were on SSA + Pegvisomant (PEG) and one (5%) was on SSA + DA + PEG. Four patients (29%) with controlled and three patients (15%) with uncontrolled acromegaly had hypopituitarism. Two patients had hypothyroidism and hypogonadism, two had hypocortisolism and hypogonadism, one had hypogonadism, and two had hypocortisolism. They were receiving appropriate hormone replacement therapy. DHEA-SO4, total testosterone and cortisol levels were lower in cases with acromegaly (p = 0.003, p = 0.04 and p = 0.002, respectively). The median basal serum levels of FSH, LH, estradiol and HOMA-IR did not differ significantly among the groups (Table 2). Acromegaly cases with hypopituitarism had lower levels of DHEA-SO4, total testosterone and cortisol levels compared to cases without hypopituitarism (p = 0.01, p = 0.005 and p = 0.02, respectively). The total number of pregnancies was 116 (median: 4 [IQR: 2–5, min–max: 0–8]) in cases with acromegaly (controlled/uncontrolled: 49/67) and 55 (median: 2 [IQR: 1–3, min–max: 0–7]) in the HC (p = 0.01). The median number of parity was also higher, albeit rather insignificantly, in cases with acromegaly (2 [IQR: 2–4, min– max: 0–6]) compared to the HC (2 [IQR: 1–3, min–max: 0–4]) (p = 0.06) (Table 3). No difference was found in median number of previous pregnancies between controlled and uncontrolled acromegaly groups (4 [IQR: 2–5] and 3 [IQR: 2–5], respectively; p = 0.8). In all of the cases with acromegaly, pregnancies had occurred before RT. There was also no difference in the median number of parity between the controlled (3 [IQR: 2–4]) and uncontrolled (2 [IQR: 2–3]) cases of acromegaly (p = 0.5). Cases with acromegaly had a higher incidence of miscarriages compared to the HC (0 [IQR: 0–2, min–max: 0–3] and 0 [IQR: 0–0, min–max: 0–3], p = 0.02) (Table 3). There was no difference in the median number of miscarriages between the controlled (0 [IQR: 0–1]) and uncontrolled (0 [IQR: 0–2]) acromegaly groups (p = 0.7). The number of a miscarriages was positively correlated with number of pregnancies (r = 0.8, p < 0.001). A cervical polyp was detected in one case with acromegaly who had controlled disease activity, and in none of the HC (p = 0.4). The frequency of pelvic organ prolapse (POP) was significantly higher in patients with acromegaly than in the HC (p = 0.003). The frequency of POP was similar in controlled and uncontrolled acromegaly patients (p = 0.3). There was no difference in GH and IGF-1 levels between cases with and those without POP (p = 0.3 and p = 0.7, respectively). Moreover when only cases with POP were taken into consideration, numbers of total pregnancies, parity and miscarriages were not statistically different between cases with acromegaly and HC (p = 0.2, p = 0.3 and p = 0.5). Limiting the analysis to only cases of previous pregnancy, POP was seen in 18 (60%) of 30 cases with acromegaly and in 4 (20%) of
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O. Celik et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 44–47
Table 2 HOMA-IR and hormone levels in female patients with acromegaly and healthy controls.
HOMA-IR Free T4 (ng/dL) TSH (mIU/L) Estradiol (pg/mL) FSH (mIU/mL) LH (mIU/mL) PRL (ng/mL) DHEA-SO4 (mcg/dL) Androstenedione (ng/mL) Total testosterone (ng/mL) Free testosterone (pg/mL) 17OH Progesterone (ng/mL) Cortisol (mcg/dL) GH (ng/mL) IGF-1 (ng/mL)
Acromegaly (n = 34)
Healthy controls (n = 27)
p
1.8 [0.7–3.5] 1.3 [1.2–1.4] 1.4 [0.8–2.1] 24.1 [8.6–38.5] 7.2 [4.9–30.3] 4.39 [2.3–16.5] 8.1 [0.7–15.2] 108 [71.9–142.8] 1 [0.8–1.5] 0.2 [0.1–0.2] 1 [0.7–1.3] 0.5 [0.4–0.7] 12 [9.6–15] 1.4 [0.9–2.9] 447 [328.8–749]
1.9 [0.6–3.6] 1.32 [1.17–1.36] 1.54 [1–1.95] 31.3 [19.7–52.3] 7.8 [6.1–58.9] 8.1 [5.1–25] 10.7 [8–16] 185 [129.7–252] 1.45 [0.84–1.69] 0.24 [0.18–0.31] 1.2 [0.83–1.68] 0.44 [0.35–0.53] 16 [12.8–19.1] 0.64 [0.18–1.21] 335.5 [264.5–393.3]
0.6 0.3 0.05 0.09 0.4 0.07 0.09 0.003* 0.1 0.04* 0.2 0.3 0.002* <0.001* <0.001*
Data are expressed as median and IQR. * statistically significant p values.
20 subjects in the HC (p = 0.005). Additionally, in cases with prior vaginal delivery, POP was present in 18 (60%) of 30 cases with acromegaly and in 4 (24%) of 17 of the subjects in the HC (p = 0.02). Comment In the current study, the frequencies of POP and miscarriage were greater in female cases with acromegaly. The majority of the other findings of gynecologic examination and history did not reveal an obvious difference between cases with and without acromegaly. Table 3 Findings of the gynecologic examination and history of the female patients with acromegaly and healthy controls. Acromegaly (n, %) TAHBSO Cervical polyp Myoma Menopausal findings Pelvic organ prolapse Rectocoele Cystocoele Uterine descent Combined Dysfunctional uterine bleeding Incontinence
3 1 2 12
(9%) (3%) (6%) (36%)
Healthy controls (n,%)
p
0 0 0 10
0.1 0.4 0.2 0.3
(0%) (0%) (0%) (37%)
18 (53%) 1 (6%) 7 (39%) 1 (6%) 9 (50%) 1 (3%) 4 (12%) (3 mixed type and 1urge type)
4 (15%) 3 (11%) 1 (4%) 0 (0%) 0 (0%) 0 (0%) 4 (15%) (1 mixed and 3 stress type)
116 4
55 2
Number of parity Total Median
88 2
47 2
Number of miscarriages Total Median
29 0
8 0
Mode of delivery Vaginal C/S Unknown
30 (88%) 1 (3%) 3 (9%)
Number of pregnancies Total Median
0.003**
0.4 0.7
0.01**
0.06
0.02**
0.07 17 (63%) 3 (11%) 7 (26%)
TAHBSO Total abdominal hysterectomy with bilateral salpingo-oophorectomy, C/S cesarean section. ** statistically significant p values.
POP is the descent of pelvic organs into the vaginal canal and occurs with advanced age and vaginal parity [11–13]. It is associated with pelvic floor dysfunction and constitutes a major health problem, especially for women above 50 years old [14]. Menopause, obesity and cigarette smoking constitute additional risk factors for POP [15–17]. Its prevalence varies between 25% and 97% of the population [18]. In this study, fewer HC had POP (4/27 (15%)) compared to what has previously been reported. The mean age of the two groups was less than 50 so this could explain why the frequency of POP was lower in our HC. Cases with acromegaly, however, had increased frequency of POP compared to the HC. Since mean age, BMI, menopausal status and smoking history were similar in the two groups, these risk factors were eliminated as sources of higher POP in cases with acromegaly. Increased numbers of pregnancies in cases with acromegaly could be responsible for POP; nevertheless, the numbers of parity and mode of deliveries were similar in the groups. Moreover in cases with POP the number of pregnancies, parity and miscarriages did not differ between cases with acromegaly and HC, meaning that the increased incidence of POP in acromegaly may not be related to the number of pregnancies, parity or miscarriages. Additionally, when all the subjects with prior pregnancy were taken into consideration, it was seen that the frequency of POP was still greater in acromegaly cases than in the HC. Similarly, among those with prior vaginal birth, women with acromegaly had a higher incidence of POP than in the HC. This means that, in addition to preexisting factors including previous pregnancy and vaginal parity, GH and/or IGF-1 excess could be also a risk factor for POP. There was no difference, however, in the occurrence of POP between the controlled and uncontrolled cases with acromegaly, so POP may be an irreversible outcome of excessive GH/IGF-1 secretion. Damage to the pelvic floor neuromusculature and connective tissue has been suggested as a causative factor of POP [19]. GH may alter the composition of the extracellular matrix and acromegaly is known to cause valvular and aortic root changes comparable with the connective tissue disease, Marfan’s syndrome [20,21]. Moreover, acromegaly has been linked with diverticular disease due to irreversible changes in the collagen of the colon [22]. It may therefore be speculated that in addition to the wellknown effects of GH and IGF-1 on various tissues, GH and IGF-1 may also weaken pelvic floor connective tissue. In the majority of cases in this series, pregnancies had occurred before diagnosis of acromegaly and RT, so our data are insufficient to draw a conclusion about the impact of acromegaly or RT on fertility. Nevertheless, it is interesting that there was a total of 116 pregnancies in 34 women with acromegaly, which is a strikingly
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high incidence of pregnancy. In addition, cases with acromegaly had a higher number of pregnancies than the HC. This result could be partly explained by the socioeconomic differences between the groups, e.g., lower levels of education and being of rural origin, in cases with acromegaly. The number of pregnancies was negatively correlated with educational levels and positively correlated with rural origins (i.e., the lower the educational level, the greater the number of pregnancies. Similarly, women with rural origins were more likely to have higher number of pregnancies). Although cortisol, DHEA-SO4 and total testosterone levels were lower in acromegaly, their levels were not sufficiently low to have clinical significance. Hypopituitarism may have contributed to lower levels in the acromegaly group compared to HC. There was a greater number of miscarriages in cases with acromegaly than in the HC. This is not surprising when broad and possible effects of GH/IGF-1 excess are considered. This effect, however, may be an irreversible outcome of acromegaly since number of miscarriages did not differ according to disease activity and was not associated with GH or IGF-1. Moreover, the higher incidence of miscarriages may be associated with greater numbers of pregnancies, but the reason for miscarriage in the current cohort is unknown. The absolute prevalence of miscarriage in cases with acromegaly can be established by further studies involving increased numbers of cases. To our knowledge, this is the first controlled study evaluating gynecologic findings in female cases of acromegaly, specifically POP. Acromegaly may affect pelvic structures and facilitate the occurrence of pelvic organ prolapse, and may therefore cause additional health issues and reduce quality of life in female patients. Conflict of interest statement The authors declare no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported. Funding The study was supported by the Research Fund of the University of Istanbul. Istanbul, Turkey, Project No. 13244. Condensation Acromegaly causes additional health issues and reduces quality of life in female patients by affecting pelvic structures and facilitating the occurrence of pelvic organ prolapse.
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