Endometrial morphology and pituitary-gonadal axis dysfunction in women of reproductive age undergoing chronic haemodialysis—a multicentre study

Joanna Matuszkiewicz-Rowinska1, Katarzyna Skórzewska2, Stanislaw Radowicki2, Stanislaw Niemczyk3, Antoni Sokalski4, Jerzy Przedlacki1, Janusz Puka5, Marek Switalski6, Kazimierz Wardyn1, Janusz Grochowski7 and Kazimierz Ostrowski1

1 Department of Internal Medicine and Nephrology, 2 Department of Gynaecological Endocrinology, the Medical University of Warsaw, 3 Dialysis Unit, Wolomin Hospital, Wolomin, 4 Dialysis Unit, Radom Hospital, Radom, 5 Dialysis Unit, Praski Hospital, Warsaw, 6 Department of Nephrology, Plock Hospital, Plock, Poland and 7 Dialysis Unit, Maków Mazowiecki Hospital, Maków Mazowiecki, Poland

Correspondence and offprint requests to: Joanna Matuszkiewicz-Rowinska, Department of Internal Medicine and Nephrology, The Medical University of Warsaw, Poland. Email: jotmatrow{at}tlen.pl



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Although disorders of the reproductive system are very common in women undergoing chronic haemodialysis, this issue remains a neglected area. The aim of the study was to evaluate the endometrial morphology and its relationship with pituitary-gonadal axis dysfunction in uraemic women of reproductive age undergoing haemodialysis.

Methods. The baseline survey with determination of the sex hormones concentrations was performed in 75 haemodialysed women aged 18–45 years. The control group consisted of 33 healthy premenopausal women, aged 18–45 years, with normal menstruation. Then, 40 haemodialysis women, who met the inclusion criteria and gave their informed consent, underwent endometrium suction biopsy.

Results. The pathological endometrial morphology was observed in 80% of biopsied subjects. Atrophia or subatrophia was recognized in almost half of the cases, and proliferative changes in one-third of them. Full atrophia with no mitotic figures was found in all but one non-menstruating woman. In one case, adenocarcinoma in situ was diagnosed and successfully treated. The analysis of the relationship between hormonal status and endometrial morphology revealed the substantial influence of oestradiol on endometrium as a target organ. In women with atrophic changes, oestradiol concentrations were significantly decreased, whereas in the remaining subjects, the increase of serum oestradiol seemed to be accompanied by a shift in endometrium morphology from secretional pattern, through proliferative changes to glandular hyperplasia. Mean serum 17-ß oestradiol was decreased in women with amenorrhoea, and increased in those with eumenorrhoea (P<0.001). Except women with regular menses, mean serum progesterone concentrations were in the lower normal range. Seventy-five percent of the studied population had menstrual disorders, and amenorrhoea constituted almost a half of them.

Conclusions. Pathological endometrium morphology is very common in uraemic women of reproductive age undergoing haemodialysis, with proliferative changes in one-third and atrophia in almost a quarter of them. The results of the study suggest a preserved normal reactivity of endometrium on circulating oestrogens.

Keywords: endometrium; end-stage renal disease; haemodialysis; menstrual disturbances; pituitary-gonadal dysfunction; sex hormones



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The reproductive system disorders are commonly encountered in adults of both sexes with end-stage renal disease. The majority of premenopausal women undergoing long-term dialysis therapy experience anovulation, abnormal menstrual cycles, often associated with amenorrhoea, loss of libido and inability to reach orgasm [1–4]. Their sexual activity is usually reduced. All those symptoms may significantly contribute to depression, often observed in this group of patients. However, despite the great progress in our knowledge of the pathophysiology of uraemia, gynaecological and sexual issues remain a poorly understood and neglected area. There is very little information about menstrual patterns, their relationship to changes in patient's endocrine status, and studies on endometrial morphology in this population are lacking.

The aim of the study was to evaluate the endometrial morphology and its relationship with pituitary-gonadal axis dysfunction in uraemic women of reproductive age undergoing haemodialysis.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
A baseline survey was performed in 75 premenopausal women, aged 18–45 years (mean age (35±8 years), undergoing haemodialysis at least for 3 months in six dialysis units from Mazovian district. Fifty two of them were receiving recombinant human erythropoietin (rHuEpo). No one had been treated with sex hormones or corticosteroids for at least 5 years. The control group consisted of 33 healthy premenopausal women, aged 18–45 years (mean 35±6 years) with normal menstruation. All subjects underwent a careful general and gynaecological examination and their sex hormones serum profile was determined.

Forty women who gave an informed consent entered the second part of the study. The exclusion criteria were infection of the genital tract and clotting disorders. In all of the subjects, the endometrium biopsy was performed, in the menstruating women in the luteal phase. The procedure was done in the outpatient clinic, without anaesthesia, with the Pipelle endometrial sampling device (Unimar, Wilton, CT), through the undilated cervix. The protocol of the study was approved by the Warsaw Medical School Ethical Commitee.

In menstruating women, serum samples for prolactin, follicle stimulating hormone (FSH), luteinizing hormone (LH) and 17-ß oestradiol concentrations determinations were taken on the sixth to eighth day of the cycle (follicular phase in normal cycle), and for progesterone and testosterone concentrations 4–6 days before anticipated menses (luteal phase in normal cycle). In non-menstruating women, serum sex hormones concentrations were measured once, on the same day the biopsy was performed. The menstrual cycles lasting 28–32 days were classified as normal, shorter ones as polymenorrhoea, and longer ones as oligomenorrhoea. Absence of menses for at least 6 months was diagnosed as amenorrhoea secundaria. In women who had not been menstruating for more than 3 months but less than 6 months a progestin stimulation test was performed. In the case of lack of menses in 3 weeks after medroksyprogesterone acetate administration (50, 50 and 25 mg i.m., in the first, second and third day) the woman was classified as having amenorrhoea. The serum samples were stored at –20°C until analysed. Serum concentrations of 17b-oestradiol (premenopausal range for follicular phase 25–75 pg/ml, post- menopausal range <20 pg/ml), prolactin (normal range = 66–490 mIU/ml), LH (premenopausal range 1.2–12.5 mIU/ml, postmenopausal 14–48 mIU/ml), progesterone (premenopausal range for luteal phase 7.6–81.0 nmol/l, postmenopausal 0.8–3.8 nmol/l) and testosterone (normal range 0.10–0.96 ng/ml) were measured by immunoradiometric assay (Delfia LKB, Pharmacia, Finland), and serum FSH (premenopausal range 3.2–10.0 mIU/ml, postmenopausal 36–138 mIU/ml) by the immunoenzyme method (Serozyme, Serono, Switzerland).

All results are presented as means±SD. Student's t-test for paired variables and {chi}2 test for the differences in categorical data were used. P<0.05 was taken as significant.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The pathological changes in endometrium morphology were observed in 80% of biopsied subjects. Even in women with regular menses, normal luteal phase morphology (stadium secretionis) or slightly delayed endometrial dating (stadium praesecretionis) was observed in 43% of cases only (Table 1), while 36% of them had more or less pronounced proliferative changes. Full atrophia with no mitotic figures was only diagnosed only and in almost all non-menstruating women; it was often accompanied by vaginal atrophy, dryness and pruritus. In one case, adenocarcinoma in situ was diagnosed and successfully treated.


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Table 1. Endometrial morphology in the studied women in relation to their menstrual disturbances

 
The hormonal profile of the studied women in relation to their endometrial morphology is shown in Table 2. The most profound disturbances in serum pituitary-gonadal profile were noted in nine cases of atrophic endometrium, with markedly increased mean serum prolactin, LH and FSH, decreased serum 17-ß oestradiol and mean serum progesterone in the lower normal range. On the contrary, women with stadium secretionis/presecretionis tended to have a normal hormonal profile, with the mean sex hormones concentrations within the normal range. The remaining pathomorphological patterns were associated with increased serum 17-ß oestradiol, the highest in women with glandular hypertrophy (P<0.002 in comparison with those with atrophic changes). Except for women with a typical secretional pattern, mean serum progesterone concentrations tended to be low, with the lowest values in women with endometrial atrophia (P<0.05 in respect to the control group). The only significant difference (P<0.05) observed in serum testosterone concentration concerned patients with glandular hypertrophy (highest values) and atrophia (lowest values).


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Table 2. Hormonal profile of the studied women in relation to their endometrial morphology

 
The main clinical characteristics and the hormonal status in relation to the menstrual disturbances of the women who took part in the baseline survey are shown in Table 3. No differences in hormonal status between subjects receiving and not receiving rHuEpo were observed. Increased serum prolactin concentrations were noted in 51% of all haemodialysed women (in 72% with amenorrhoea and 20% with eumenorrhoea). Mean serum FSH and LH were increased only in patients with amenorrhoea, but they were generally higher in haemodialysis women than in the control group. Mean serum 17-ß oestradiol was decreased in women with amenorrhoea, and increased in the subjects with oligomenorrhoea and eumenorrhoea. Except women with regular menses, mean serum progesterone and testosterone concentrations were in the lower normal range. Seventy-five percent of the studied population had menstrual disorders (Figure 1), and amenorrhoea constituted almost half of them. Among women with amenorrhoea, this disturbance had lasted from the predialysis period; in only five cases those subjects were older (mean age 42±4 years). In 18 out of the remaining 20 women, the menstruation had been restored after the initiation of maintenance dialysis and stopped again 14–51 months later. There were no differences in age, duration of dialysis therapy and dialysis dose among the women with a different menstruation pattern.


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Table 3. The main characteristics, hormonal status and their relationship with menstrual disturbances in the whole studied population

 


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Fig. 1. Menstrual disturbances in the whole studied population.

 


   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Our study revealed the pathological changes in endometrium in the great majority of studied women; normal endometrial morphology was observed only in 20% of subjects (six with eumenorrhea and two with oligomenorrhea). Atrophia or subatrophia constituted almost half of the changes. The analysis of the relationship between hormonal status and endometrial morphology suggest a preserved normal reactivity of endometrium, as a target organ, on circulating oestrogens. In women with atrophic changes, oestradiol concentrations were significantly decreased, whereas in the remaining subjects, the increase of serum oestradiol seemed to be accompanied by a shift in endometrium morphology from secretional pattern, through proliferative changes to glandular hyperplasia. To our knowledge there are only anecdotal data concerning endometrial morphology in uraemia and no previous studies are available to compare these findings.

Our study confirms an opinion that suction endometrial biopsy is a safe, convenient and effective procedure, which can be done in the outpatient clinic, without cervical dilatation or anaesthesia. No complications were observed and pain was very little if any. It is noteworthy that the procedure allowed for detection and successful treatment of early endometrial cancer in one subject. A recent meta-analysis revealed that outpatient endometrial biopsy has a high overall accuracy in detection of endometrial cancer and atypical hyperplasia when an adequate specimen is obtained [5].

The most interesting finding in the hormonal profile of the whole studied population was that only 33% of studied women were found to be hypooestrogenic, which is in contrast to most of other studies in which reduced serum oestrogen concentrations were found in the majority of dialysed women [1,3,4,6,7]. Our study revealed that in many of the subjects serum oestrogen concentrations were increased or in the upper range. The combination of relatively low serum progesterone with high serum oestrogen, can result in incomplete maturation of the endometrium followed by hypermenorrhoea and dysfunctional bleeding. Moreover, high serum oestrogen concentrations, unopposed by adequate serum progesterone, create a situation of relative progesterone deficiency. This can stimulate endometrial hyperplasia and pose the risk of endometrial cancer. There are some suggestions that risk of uterine cancer may be increased in the uraemic population [8]. The administration of a progestin in the second part of the menstrual cycle could be an interesting option for these women. This argues for screening this population for hyperoestrogenemia.

In the first part of the study only 27% of the studied subjects had regular menses. This is much less than reported by Holley et al. [1], who found 42% of premenopausal haemodialysis women menstruating regularly. One could argue that the difference could result from a smaller percentage of women taking rHuEpo in our study (69 vs 90% in the study of Holley et al.), since there are some data indicating that the use of rHuEpo substantially improves sexual function [9]. However, contrary to expectations, no differences in hormonal status and presence of eumenorrhoea between patients treated and untreated with rHuEpo were observed.

There was a clear relationship between menstrual disturbance and hormonal profile. Most of the studied women with regular menses had normal serum gonadotropins, increased serum oestrogen, with relatively low serum progesterone concentration, and serum prolactin in the upper normal range, whereas amenorrhoea was predominantly accompanied by an abnormal pituitary-gonadal axis with the highest serum prolactin, increased LH and FSH, and the lowest, mostly reduced gonadal hormones concentrations. The equal increase of both gonadotropins, without a rise in LH/FSH ratio typical for premenopausal uraemic women, is noteworthy and suggests the premature menopausal status of those subjects. The oestrogen depletion could be an important additional risk factor of developing accelerated uraemic bone disease, however, studies on this issue are lacking. In our small preliminary study, hormonal replacement therapy inhibited bone demineralization in hypooestrogenic women of reproductive age undergoing haemodialysis; these results certainly require confirmation in larger groups of patients [10].

In conclusion, pathological changes in endometrium are very common in uraemic women of reproductive age undergoing haemodialysis—normal endometrial morphology was observed in only 20% of subjects, and atrophia in almost a quarter of them. The analysis of the relationship between hormonal status and endometrial morphology revealed the substantial influence of oestradiol on endometrium as a target organ. In our study, a suction endometrial biopsy was a safe and convenient procedure, which can be done in the outpatient clinic, without cervical dilatation or anaesthesia.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Holley JL, Schmidt RJ, Bender FH, Dumler F, Schiff M. Gynaecologic and reproductive issues in women on dialysis. Am J Kidney Dis 1997; 29: 685–690[ISI][Medline]
  2. Mastrogiacomo I, DeBesi L, Serafini E et al. Hyperprolactinemia and sexual disturbances among uremic women on hemodialysis. Nephron 1984; 37: 195–199.[ISI][Medline]
  3. Bommer J. Sexual disorders. In: Davidson AM, Cameron JS, Grunfeld J-P, Kerr DNS, Ritz E, Winearls CG, eds. Oxford Textbook of Clinical Nephrology. Oxford University Press, Oxford: 1998; 1866–1884
  4. Ginsburg ES, Owen WF Jr. Reproductive endocrinology and pregnancy on women on hemodialysis. Semin Dial 1993: 6: 105–116[ISI]
  5. Clark TJ, Mann CH, Shah N et al. Accuracy of outpatient endometrial biopsy in the diagnosis of endometrial cancer: a systematic quantitative review. BJOG 2002; 109: 313–316[ISI][Medline]
  6. Michaelides N, Humke W. Erfahrungen bei der gynäkologischen Betrteuung von Patientinnen mit chronischer Niereninsuffizienz. Nieren- und Hochdruckkrankheiten 1993; 22: 187–192[ISI]
  7. Lim VS. Reproductive function in patients with renal insufficiency. Am J Kidney Dis 1987; 9: 363–367[ISI][Medline]
  8. Stehman-Breen C. Estrogen deficiency in ESRD: to treat or not to treat? In: Xth Annual Spring Clinical Nephrology NFK Meeting, 2001
  9. Schaefer RM, Kokot F, Wernze H, Geiger H, Heidland A. Improved sexual function in hemodialysis patients on recombinant erythropoietin: a possible role of prolactin. Clin Nephrol 1989; 31: 1–5[ISI][Medline]
  10. Matuszkiewicz-Rowiñska J, Skórzewska K, Radowicki S et al. The benefits of hormone replacement therapy in pre-menopausal women with oestrogen deficiency on haemodialysis. Nephrol Dial Transplant 1999; 14: 1238[Abstract]
Received for publication: 27. 6.03
Accepted in revised form: 4. 2.04





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