Polycystic Ovary Syndrome and Hyperprolactinemia Are Distinct Entities

Written By: Sam Savage

Published Date: July 13, 2007 Last Edited: July 13, 2007

By Filho, Roberpaulo Barboza Domingues, Lucilia; Naves, Luciana; Ferraz, Elenice; Et al

Abstract The aims of the present study were to identify the cause of hyperprolactinemia in polycystic ovary syndrome (PCOS) and to compare prolactin (PRL) levels between PCOS women without hyperprolactinemia and women with insulin resistance and without PCOS. A group of 82 women (age: 27.1 +- 7.6 years) with PCOS was included in the study. Their PRL levels were measured and compared with those of women with insulin resistance without PCOS (controls; n = 42; age: 29.2 +- 8.2 years). Among the 82 PCOS women, 13 (16%) presented high PRL levels (103.9 +- 136.0 [mu]g/l). The causes of hyperprolactinemia were: pituitary tumor (responding to cabergoline) in nine cases (69%; PRL range: 28.6-538 [mu]g/l); oral hormonal contraceptive treatment in two cases (15%; PRL: 46 and 55 [mu]g/l, respectively); and use of buspirone and tianeptine in one case (8%; PRL: 37.1 [mu]g/l); one case (8%; PRL: 34.4 [mu]g/l) had macroprolactinemia. In drug-induced hyperprolactinemic patients PRL levels normalized after treatment interruption. The average PRL level in the 69 remaining patients was 12.1 +- 5.5 [mu]g/l, a value not statistically different from that of the control group (11.8 +- 4.9 [mu]g/l). This result leads us to conclude that PCOS patients with increased PRL levels must be investigated for other causes of hyperprolactinemia, because hyperprolactinemia is not a clinical manifestation of PCOS.

Keywords: Hyperprolactinemia, polycystic ovary syndrome, insulin resistance, ovary, macroprolactinemia

Introduction

Polycystic ovary syndrome (PCOS) is the most frequent endocrine disorder among women at reproductive age [1,2]. This syndrome is frequently associated with obesity, menstrual irregularity, infertility, hirsutism and insulin resistance [3]. Hyperinsulinemia is present in patients with PCOS, the result of the body’s attempt to compensate its resistance to insulin. Hyperinsulinemia plays an important role in the physiopathology of PCOS because it stimulates ovarian androgen production, reduces circulating levels of sex hormone-binding globulin and inhibits ovulation [4,5] .

Similarly to PCOS, hyperprolactinemia, either of tumor origin or due to the use of medications, may also cause chronic anovulation and the appearance of polycystic ovaries upon ultrasonographic examination [6-10] . Thus, many researchers associate PCOS with hyperprolactinemia. A number of literature reviews show this association, with ranges from 17 to 50% [11], 17 to 43% [12], and 3 to 67% [13]. It has been suggested that the high luteinizing hormone (LH) levels frequently observed in PCOS are due to a lack of dopamine, the main regulator of prolactin (PRL) secretion [14-16]. However, clinical studies have suggested independence between LH and PRL secretions in these patients, as dopaminergic inhibition causes increases in PRL levels without changing LH levels [17]. Furthermore, women with PCOS receiving dopamine agonists showed no alterations in LH secretion [18]. On the other hand, significantly higher PRL levels have been observed in patients with PCOS, even in those witiiout hyperprolactinemia, compared with the levels found in controls without PCOS [19].

The objectives of the present study were to identify the cause of hyperprolactinemia in patients with PCOS and to compare PRL levels between PCOS women without hyperprolactinemia and women with insulin resistance and no PCOS.

Methods

This was a case-control, retrospective analytical study involving patients widi PCOS and subjects witih insulin resistance without PCOS. The included patients had an average age of 27.1 + 7.6 years and were attending the endocrinological gynecology clinic of the Hospital Universitario de Brasilia. Group 1 included 82 women in whom PCOS was clinically diagnosed according to the following parameters: irregular menstrual cycles (secondary amenorrhea and/or oligomenorrhea) since menarche; hirsutism (Ferriman-Gallwey index score >8) and/ or acne; and presence of micropolycystic ovaries by ultrasound imaging (ten or more follicular cysts with diameter ranging from 2 to 10 mm). This group was stratified on the basis of PRL level: >27 [mu]g/l (group 2) and / =80 cm, body mass index (BMI; weight in kg divided by the square of height in m) >/=25 kg/m2, and homeostasis model assessmentinsulin resistance index (HOMA-IR) >2.7.

Basal level of 17-hydroxyprogesterone in patients with PCOS was normal (1.5 +- 1.2 nmol/1), thus excluding congenital adrenal hyperplasia.

PRL, insulin, follicle-stimulating hormone (FSH) and LH levels were analyzed by chemiluminescence methods using Immulite 2000 DPC reagents (Medlab, Sao Paulo, Brazil). Thyroid-stimulating hormone (TSH) was measured by a chemiluminescence method using ADVIA Centaur reagents (Bayer, Sao Paulo, Brazil). Glucose level was evaluated by a colorimetric enzymatic technique using ADVIA 1650 reagents (Bayer). The reference values were: PRL,

The HOMA-IR index, which assesses the level of insulin resistance, was calculated using the following formula [20]: HOMA- IR= [fasting insulin ([mu]ml) x blood glucose level (mmol/l)]/ 22.5. The HOMA-ss index, which defines the function of die ss cell, was calculated by die following formula: HOMA-j? = 20 x insulin ([mu]/ml)/ [blood glucose level (mmol/1) – 3.5].

Table I. Clinical characteristics of patients with polycystic ovary syndrome (group 1), with (group 2) and without hyperprolactinemia (group 3), and with insulin resistance (control).

Abdominal ultrasonography was utilized to diagnose micropolycystic ovaries. Magnetic resonance imaging (MRI) of the sellar region was performed whenever necessary using gadolinium as contrast medium.

The study was performed according to the Helsinki Declaration (2000) for studies in human subjects.

Statistical analysis was performed utilizing the unpaired Student t test. The level of significance was fixed at p

Results

Patient characteristics

Of the 82 patients with PCOS (group 1), 13 (16%) had PRL level >27 [mu]g/l (group 2). The following causes of hyperprolactinemia were diagnosed: pituitary tumor (PRL range: 28.6-538 [mu]g/l), established by MRI of the sellar region, in nine (69%) patients (improved by cabergoline treatment, 0.5 mg twice a week); drug- induced in three (23%) patients – two used oral hormonal contraceptives (PRL: 46 and 55 [mu]g/l, respectively) and one used buspirone and tianeptine (PRL: 37.1 [mu]g/l) – whose PRL levels normalized after withdrawing medication. The remaining patient in group 2 presented macroprolactinemia (PRL: 34.4 [mu]g/l) and required no specific treatment. Group 3 was composed of 69 (84%) patients with PCOS, with PRL levels =27 jug/1. The control group consisted of 42 patients without PCOS but with insulin resistance.

The clinical characteristics of the included patients are presented in Table I. The mean age of the control group was significantly higher than tiiat of groups 1 0 = 0.03), 2 (p = 0.03) and 3 (p = 0.04), but no significant differences were observed among these last groups. Age at menarche was not significandy different among the groups. BMI was significantly higher in the control group than in groups 1 (p = 0.0006), 2 0 = 0.01) and 3 (p = 0.001), but no significant differences were present among these three groups. Waist circumference was not significandy different among groups, while hip circumference was significantly higher in the control group than in group 1 O = O-Ol), group 2 (p = 0.02) and group 3 (p = 0.02). The waist/hip ratio was significantly higher in the control group than in groups 1 (p = 0.02) and 3 (p = 0.005), but not significandy different from that of group 2 O = 0.77).

Laboratory parameters

As shown in Table II, PRL levels in the control group and group 3 were significantly lower compared with those in groups 1 and 2 ? = 0- 03). However, no statistically significant difference was observed between group 3 and the control group 0 = 0.78) or between groups 1 and 2 0 = 0.06). LH level in the control group was lower than that in groups 1 0 = 0.002) and 3 0 = 0.004), while there were no significant differences in FSH levels among groups. The LH/FSH ratio was lower in controls than in group 1 O = 0.02), but no statistical difference was observed among the other groups. Blood glucose levels were higher in the control group than in group 2 0 = 0.003), but no significant difference was observed between die otiier groups. HOMA- IR and HOMA-/? indices were similar among groups.

Discussion

Our results showed that patients with a clinical history compatible with PCOS and with high PRL levels must be investigated for other causes of hyperprolactinemia, such as pituitary tumor, use of medications or macroprolactinemia, because hyperprolactinemia is not part of the PCOS laboratory condition. As shown in this study, PRL levels in patients with primary PCOS were not different from those of the control group with insulin resistance. These results are in agreement with previous studies reporting similar basal PRL levels between women with PCOS and normal controls [11,12,21-24]. Furthermore, Venturoli and colleagues [21] showed no differences in either mean PRL levels or PRL pulsatility between women with PCOS and normal controls. On the other hand, Bahceci and associates [19], in disagreement with our observations and previously quoted results, reported that patients with PCOS showed significantly higher PRL levels than a control group: 18.4 +- 8.4 vs. 14.0 +- 4.0 [mu]g/l p

In several other studies, an association between PCOS and hyperprolactinemia has been described with the following frequencies: 7% [16], 13% [26], 17% [27], 22% [28], 28% [29] and 30% [30,31]. Alterations in the lactotrophic function in patients with PCOS have been suggested by a number of authors [28,31-37]. An increased PRL response to TRH has also been described in PCOS [35], a condition which could be predictive of the response of PCOS patients to bromocriptine [32,34]. However, these observations are not corroborated by other authors [H]. Falaschi and co-workers [38] showed that the PRL responses to TRH and haloperidol (a dopamine antagonist) were similar in PCOS patients without hyperprolactinemia and normal women, whereas only the hyperprolactinemic PCOS patients reacted with an excessive PRL discharge. In addiction, the PRL response to both secretagogue agents was blunted in patients with galactorrhoea and amenorrhea, condition defined by some authors as idiopathic hyperprolactinemia due to the normal radiographic image of the sella turcica [38] . These observations suggest that PCOS and other hyperprolactinemia states are distinct conditions.

According to data presented in this study, one could suppose that die association described by these authors could be biased because the origin of the hyperprolactinemia was not systematically investigated; in particular, image resources (like MRI, capable of detecting a 3-mm microadenoma) were not utilized [39,40] sometimes because the investigations were conducted before the availability of sophisticated imaging techniques [41] such as highresolution computed tomography (CT) or MRI. As shown in Figure 1, a small pituitary tumor localized above the sellar floor can be demonstrated by MRI but it cannot be seen by X-ray or former CT machines.

The high PRL basal levels in women with PCOS compared with tiiose of control women [42] can be explained by analyzing the data of the present study. This observation may be due to the increase in basal PRL levels in women with polycystic ovaries (group 1) that we have observed, which is in agreement with previously published data suggesting that these women would have higher PRL levels in relation to normal women. However, when patients with a compatible clinical history with PCOS but with welldefined causes of hyperprolactinemia (group 2) were separated from those with normoprolactinemia (group 3), the latter presented values similar to those observed in the control group with insulin resistance.

Another possibility to explain die reported association between PCOS and hyperprolactinemia could be the presence of macroprolactinemia [43] . In the present study among patients wim PCOS and hyperprolactinemia, one presented macroprolactinemia as cause for the elevation in circulating PRL levels. This cause of hyperprolactinemia has almost never been investigated. In a retrospective study, Suliman and collaborators [44] demonstrated that frequently patients with hyperprolactinemia are submitted to inadequate investigation. For example, these audiors observed that 87% of the patients widi hyperprolactinemia due to macroprolactin received unnecessary treatment with dopaminergic agonists [44] . A retrospective study among 109 patients with a history of chronic anovulation and signs of androgen hypersecretion revealed elevated PRL levels in eight of them [45]. More detailed investigation on the origin of hyperprolactinemia indicated the presence of macroprolactinemia in four of these patients. This information further stresses the necessity of investigating more thoroughly patients with PCOS associated with hyperprolactinemia, always including the evaluation of macroprolactin.

Figure 1. A small pituitary tumor localized near the pituitary stalk demonstrated by magnetic resonance imaging that may not be observed in the simple X-ray or earlier computed tomography image.

Possibly, the wrong inclusion of PCOS as a possible cause of high PRL levels began with the publication of the classic work of Forbes and colleagues [46], in which the association among galactorrhea, amenorrhea and the polycystic ovary was described. Other authors have confirmed these observations, describing the association between galactorrhea and polycystic ovary in some infertile women [47,48] . This misunderstanding is based on the fact that women with chronic anovulation from other etiologies may present multicystic ovarian images during an ultrasound examination [6-10]. Moreover, some women with prolactinoma also present amenorrhea-associated hirsutism [16,48] like women with PCOS.

A theory advanced to explain PCOS-associated hyperprolactinemia is the lack of hypothalamusoriginated dopamine in patients with this syndrome. Dopamine infusion in pharmacological doses (4 [mu]g/ kg per min) in patients with PCOS has been reported to reduce LH secretion more intensely than in normal women [15]. However, these data were not confirmed by other authors [49] with the same experimental approach. Even dopamine infusions in doses considered as physiological did not produce differences in the LH responses in women with PCOS and normal controls [49] .

Bromocriptine, a dopamine agonist widely used to treat hyperprolactinemia, was also used in the treatment of PCOS with conflicting results [50]. Double-blind randomized studies against placebo did not demonstrate a higher effect of bromocriptine vs. placebo in the PCOS treatment [11,12,18,5155] . This finding, in agreement with the observations of the present study, indicates that patients with PCOS do not respond to bromocriptine treatment because they do not have alterations in hypothalamic dopamine secretion. However, it should be mentioned that some uncontrolled studies [53,56,57] and case reports [58-61] have demonstrated the return of menstrual cyclicity in patients with PCOS treated with bromocriptine.

In conclusion, our data show the importance and necessity of systematic investigation on die origin of hyperprolactinemia in women with chronic anovulation in order to distinguish it from PCOS. In all of the women with a history compatible with PCOS and with hyperprolactinemia, a well-defined cause for the high PRL level was identified: tumors, drugs or the presence of macroprolactinemia. Furthermore, this investigation also shows that the PRL levels in patients with PCOS are similar to those found in women with insulin resistance.

Acknowledgements

We would like to thank Adewale Adeniyi for technical assistance.

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ROBERPAULO BARBOZA FILHO1, LUCILIA DOMINGUES2, LUCIANA NAVES3, ELENICE FERRAZ2, ADRIANA ALVES3, & LUIZ AUGUSTO CASULARI3

1 Endocrinology and Neurology Clinics – CLINEN, Brasilia, Brazil, 2Department of Obstetrics and Gynecology, University of Brasilia, Brasilia, Brazil, and Endocrinology Service, University of Brasilia, Brasilia, Brazil

(Received 26 September 2006; revised 18 February 2007; accepted 21 February 2007)

Correspondence: L. A. Casuiari, CLINEN – Ed. America Office Tower, SCN quadra 1 bloco F salas 1105/?06, CEP 70911-905, Brasilia DF, Brasil. Tel/Fax: 55 61 33280228. E-mail: [email protected]

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