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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 8 2731-2735
Copyright © 1999 by The Endocrine Society

Original Studies

Menstrual Irregularity in Women with Acromegaly

G. A. Kaltsas, J. J. Mukherjee, P. J. Jenkins, M. A. Satta, N. Islam, J. P. Monson, G. M. Besser and A. B. Grossman

Department of Endocrinology, St. Bartholomew’s Hospital, London, United Kingdom EC1A 7BE

Address all correspondence and requests for reprints to: Prof. A. B. Grossman, Department of Endocrinology, St. Bartholomew’s Hospital, London, United Kingdom EC1A 7BE. E-mail: a.b.grossman{at}mds.qmw.ac.uk


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Menstrual irregularity is common in women with acromegaly, occurring in 40–84%. Although it has been attributed to gonadotropin deficiency and/or PRL excess, it has not been evaluated in detail, and its pathogenesis is not well understood. To explore the various possible pathogenic mechanisms, we have analyzed the clinical, endocrinological, and radiological characteristics of 47 women with active acromegaly within the reproductive age range (15–41 yr) with respect to their menstrual pattern; 9 patients (19%) had normal cycles, 7 (15%) had oligomenorrhea, 29 (62%) had amenorrhea, and 2 (4%) had polymenorrhea. Compared to patients with normal cycles (n = 9), patients with menstrual irregularity (oligo/polymenorrhea or amenorrhea; n = 38) were more hirsute, had lower serum estradiol (normal: median, 76.5 pmol/L; range, 20–570; menstrual irregularity: median, 283; range, 140–431; P < 0.01), and sex hormone-binding globulin (SHBG; normal: median, 19.6 nmol/L; range, 5–52; menstrual irregularity: median, 48; range, 18–60; P < 0.01), but similar testosterone levels; in addition, patients with amenorrhea had higher serum GH (normal: median, 100 mU/L; range, 8.8–400; amenorrhea: median, 30; range, 10.7–120; P < 0.05). PRL levels in excess of 1000 mU/L were found in 16 of the 38 patients with menstrual irregularity compared to only 1 of the 9 patients with normal cycles. Patients with menstrual irregularity had a greater impairment of anterior pituitary function than patients with normal cycles. Acromegalic patients who were defined as estrogen sufficient (estradiol, >140 pmol/L) had clinical baseline endocrine profiles and LH responses to GnRH stimulation similar to those in patients with polycystic ovarian disease. There was a positive correlation between GH levels and tumor size (r = 0.35; P < 0.05) and an independent inverse correlation between GH and SHBG levels (r = -0.6; P < 0.01), which persisted even in patients who were estrogen sufficient, but there was no correlation between GH and estradiol levels; in addition, there was a negative correlation between estradiol levels and tumor size (r = -0.42; P < 0.05). Thirty-five of the patients with menstrual irregularity had meso- or macroadenomas and 3 had microadenoma, whereas 6 of the 9 patients with normal cycles had microadenomas. In conclusion, menstrual irregularity is common in women with acromegaly (81% of our patients). Amenorrheic patients have higher GH levels, are mainly estrogen deficient, and tend to have larger tumors than patients with normal cycles. However, the independent negative correlation between GH and SHBG levels suggests that GH may, directly or indirectly, lead to a fall in SHBG, possibly determined by the hyperinsulinemia known to occur in acromegaly. Low SHBG levels may contribute to the menstrual disturbance seen in acromegaly in addition to any gonadotropin deficiency or hyperprolactinemia and may account for hirsutism in the presence of normal testosterone levels.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ACROMEGALY is a chronic and multisystemic disease, with an estimated prevalence of 30–40 cases/million (1, 2) and a mean age at presentation in women of 44 yr (1, 2, 3). Although menstrual irregularity is a commonly associated and occasionally presenting symptom in women with acromegaly, with an estimated prevalence of 50–75% (1, 2, 3), its pathogenesis remains unclear (4, 5). Complete or partial gonadotropin deficiency (2, 5) and hyperprolactinemia have been suggested as possible mechanisms (2, 4, 5, 6). However, acromegalic women with menstrual irregularity who retain normal gonadotropin and estrogen concentrations have also been described (4, 7, 8). Acromegaly has a known association with the polycystic ovarian syndrome (PCOS) (9), and thus, a pathogenic mechanism similar to that of PCOS might also be involved.

As acromegaly is a relatively rare disease, with the majority of female patients tending to present later in life, there has been little information in the literature concerning the detailed endocrine alterations during the reproductive lifespan (15–41 yr). We have therefore investigated the endocrinological profiles of all women presenting with acromegaly to our department in the years 1970–1993 and have correlated their endocrine and radiological features according to their menstrual histories.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

We evaluated all female patients with acromegaly within the reproductive age range (defined as 15–41 yr to minimize the inclusion of peri- and postmenopausal women whose endocrine features may have been obscured by concomitant anterior pituitary insufficiency); endocrine data were available for analysis in 47. The diagnosis of acromegaly was based on the presence of clinical symptoms and signs of GH excess and a failure to suppress GH levels below 0.5 mU/L after a 75-g oral glucose tolerance test (10). The following clinical information was recorded: age and body mass index (BMI; kilograms per m2), symptoms and/or signs of hyperandrogenism (hirsutism, acne, and male pattern hair loss), galactorrhea, and symptoms and/or signs of estrogen deficiency (hot flushes, reduced libido, and vaginal dryness). The menstrual pattern was defined as normal (every 21–35 days), oligomenorrhea (35 days to 6 months), amenorrhea (>6 months), and polymenorrhea (<21 days). Hirsutism was graded as absent, mild, moderate, or severe. Galactorrhea was graded as either present or absent. Complete endocrine evaluation consisted of baseline serum hormonal measurements at 0900 h for cortisol, T4, T3, TSH, PRL, LH, FSH, estradiol (E2), progesterone, testosterone, sex hormone-binding globulin (SHBG), and GH day-curve levels (mean of 5 samples), and in some patients dynamic endocrine tests: the insulin tolerance test for assessment of the cortisol response, and TRH and GnRH stimulation tests (10).

Methods

Hormonal measurements were performed using standard immunoassays in the Department of Chemical Endocrinology at St. Bartholomew’s Hospital. A normal cortisol response to adequate hypoglycemia was considered a cortisol peak of 580 nmol/L or above. A TSH rise of more than 2 mU/L to greater than 3.4 mU/L in response to TRH stimulation, with the 20 min value higher than the 60 min value, was considered as normal, while the FSH and LH response to GnRH stimulation was considered normal when the serum FSH and LH levels obtained 20 and 60 min after the administration of GnRH were between 1–11 and 15–42 mU/L and 1–25 and 12–35 mU/L, respectively, and exaggerated when the serum LH levels obtained at 60 min were greater than 50 mU/L in the presence of sufficient estrogen levels (10). All hormonal measurements in women with regular menstruation were performed in the follicular phase of the menstrual cycle combined with relevant progesterone measurement. Hormonal measurements derived from 150 normally menstruating women were used for comparison (control group) as well as those from a group of patients with PCOS (n = 150). The diagnosis of PCOS was based on the presence of symptoms/signs of hyperandrogenism (hirsutism, acne, and male-type alopecia), menstrual irregularity, and some or all of the following: elevated serum testosterone, androstenedione and/or dehydroepiandrosterone sulfate, and LH levels and reduced SHBG levels (10). Ovarian ultrasonography was performed in 98 women with PCOS; the diagnosis of PCOS was based on the presence of at least 10 follicles, 2–10 mm in diameter, and an increased amount of stroma with an ovarian volume greater than 6 mL in nulliparous and greater than 8 mL in parous women.

Pituitary imaging was performed with standard skull radiology and pneumoencephalography (period between 1970–1983) and computed tomography and/or magnetic resonance imaging scanning (period between 1983–1993, respectively). The GH-secreting adenomas detected on pituitary imaging were divided according to size as: microadenomas, when the adenoma was within the pituitary fossa (<1 cm) and no lateral or suprasellar extension was seen; mesoadenomas, when the pituitary fossa was expanded but there was no significant suprasellar extension; and macroadenomas, when there was substantial suprasellar or lateral extension and/or compression of the optic chiasm.

Statistical analysis

All data were analyzed using the Mann-Whitney U test of statistical significance for nonparametric data. Correlation analysis was performed using Spearman’s correlation coefficient. P < 0.05 was taken to indicate statistical significance.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Menstrual pattern

Of 47 women with acromegaly, 9 (19%) presented with normal menstrual patterns and 38 (81%) with menstrual irregularity [7 (15%) with oligomenorrhea, 29 (62%) with amenorrhea, and 2 (4%) with polymenorrhea]. Amenorrhea was the principal symptom at presentation in 5 patients (11%).

Other related clinical features

Hirsutism was noted in 26 of the 47 acromegalic women (55.5%). Other symptoms/signs suggestive of androgen excess were also relatively common (acne in 17% and male pattern alopecia in 6.4%). Patients with menstrual irregularity had a lower BMI (24.3 vs. 27.1 kg/m2; P < 0.05) and were more hirsute than patients with normal cycles. Galactorrhea occurred in 16 women with menstrual irregularity compared to 1 patient with normal cycles. Patients with menstrual irregularity also exhibited a higher prevalence of symptoms of estrogen deficiency compared to women with normal cycles.

Endocrine profiles (Table 1Go)

Compared to patients with normal cycles, patients with amenorrhea had significantly higher glucose levels, higher serum GH levels, a higher prevalence of PRL levels in excess of 1000 mU/L (14 of 29), significantly lower SHBG levels, and similar testosterone levels. Amenorrheic patients had lower baseline LH and GnRH-stimulated LH and FSH levels than patients with oligomenorrhea or those with normal cycles. Thyroid function was normal in all 9 patients with normal cycles, whereas 4 patients with menstrual irregularity (2 patients with amenorrhea) had low T4 and TSH levels or showed an inadequate TSH response to TRH stimulation in the presence of low normal T4 levels. The hypothalamo-pituitary-adrenal axis was impaired in 17 of the patients with menstrual irregularity (13 patients with amenorrhea) compared to one of the patients with normal cycles (Table 1Go).


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  		Table 1. Endocrine characteristics of women with acromegaly in the reproductive age according to their menstrual pattern (median and range are shown)

 
Using correlation analysis, there was a positive correlation between GH levels and the size of the pituitary tumor (r = 0.35; P < 0.05) and an independent inverse correlation between GH and SHBG levels (r = -0.6; P < 0.01) in all 47 patients (Fig. 1Go). There was also a negative correlation between E2 levels and the size of the pituitary tumor (r = -0.4, P < 0.05), but the positive correlation between E2 and SHBG (r = 0.3) did not reach statistical significance (P = 0.1), and there was no correlation with T4; there was no correlation between GH and E2 levels. Three of the 5 patients with normal cycles and 1 of the 2 oligomenorrheic patients who were estrogen sufficient (E2, >140 pmol/L; see below) showed an exaggerated LH response to GnRH stimulation (LH at 60 min, >50 mU/L). The SHBG levels and other endocrine parameters of all acromegalic women were also compared with the SHBG levels in 150 nonacromegalic women within the reproductive age range (15–45 yr) derived from control data within the Department of Chemical Endocrinology at our hospital. These normal values were based on women with regular menstrual cycles over the preceding 6 months, with BMI ranging between 20–30, who were not taking any medication known to affect gonadal function. The median SHBG levels in this group was 68 nmol/L (range, 38–108 nmol/L), which was significantly higher than that in acromegalic women (Table 1Go).



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  		Figure 1. Correlation of SHBG and GH in women with acromegaly (r = -0.6; P < 0.01).

 
We further divided the patients into two groups based on their serum E2 levels; those with levels within the normal range of the early follicular phase of normal women with regular cycles (E2, >140 pmol/L) were defined as estrogen sufficient, whereas those with levels below this were defined as estrogen deficient.

Patients with estrogen sufficiency state (E2, >140 pmol/L)

There were 13 patients with E2 levels above 140 pmol/L, including 9 patients with normal cycles, 3 patients with oligomenorrhea, and 1 patient with polymenorrhea.

Patients with estrogen deficiency state (E2, <140 pmol/L)

There were 27 patients with E2 levels below 140 pmol/L, including 24 patients with amenorrhea and 3 patients with oligomenorrhea.

Patients with estrogen sufficiency (Table 2Go) had higher SHBG levels and higher basal and GnRH-stimulated LH levels than patients who were estrogen deficient. However, using correlation analysis in the estrogen-sufficient patients alone, the inverse correlation between GH and SHBG was maintained (r = -0.7; P < 0.05).


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  		Table 2. Clinical, endocrine, and pituitary imaging characteristics of female acromegalic patients based on their estrogen sufficiency state (median values and range are shown)

 
Pituitary imaging (Table 3Go)

Results of pituitary imaging were available in all patients with normal cycles (1 macroadenoma, 2 mesoadenomas, and 6 microadenomas) and all patients with menstrual irregularity (30 macroadenomas, 5 mesoadenomas, and 3 microadenomas). Nine patients in total had microadenoma, 7 had mesoadenoma, and 31 had macroadenoma. Of the 38 patients with meso- or macroadenomas, 28 presented with amenorrhea.


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  		Table 3. Findings on pituitary imaging in acromegalic women of reproductive age according to their menstrual pattern at presentation

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Menstrual irregularity is common in acromegaly, ranging from 40–84% in various series (11). This wide variation in prevalence has been attributed mainly to the insidious onset of the disease and to a delay in diagnosis (1, 2, 3). In our series we found an 81% prevalence of menstrual irregularity in acromegaly, commonly associated with hirsutism, which seems to follow two particular patterns. The majority of patients had amenorrhea or oligomenorrhea associated with large tumors; these patients were mainly estrogen deficient and had complete or partial gonadotropin deficiency with or without associated hyperprolactinemia. Such a clinical, endocrine, and radiological profile is in agreement with previous studies documenting that most acromegalic patients with menstrual irregularity have either meso- or macroadenomas (1, 2), implicating gonadotropin deficiency caused by the tumor mass effect as the underlying pathogenetic mechanism (12). Hyperprolactinemia, found in approximately 30–40% of acromegalic patients (5), could also be linked with the pathogenesis, either by inducing or contributing further to gonadotropin deficiency (4, 5).

In addition, there were four patients with menstrual irregularity, three with oligomenorrhea, and one with polymenorrhea, who had smaller tumors (two micro- one meso- and one macroadenoma) than the previous group and normal estrogen levels; these patients as well as the patients with normal cycles (the estrogen-sufficient group in our series), still developed hirsutism, were gonadotropin sufficient with an exaggerated LH response to GnRH stimulation, and had reduced SHBG levels with testosterone levels in the middle normal range compared to normal menstruating women. Previous studies have also described acromegalic women presenting with either a normal menstrual pattern or oligomenorrhea and symptoms/signs of hyperandrogenism, such as hirsutism and acne (2, 4, 9, 13). The clinical and endocrinological characteristics of the estrogen-sufficient group of patients and possibly some of the patients described in previous reports (2, 4, 9, 13) are consistent with a PCOS-like picture: features of hyperandrogenism, with or without menstrual irregularity, serum E2 levels in the early follicular phase, increased free androgen levels (normal testosterone and low SHBG levels), and LH hyperresponsiveness to GnRH stimulation (9, 14, 15). Although ovarian ultrasonography was not routinely available in our analysis, several studies have demonstrated that acromegaly can induce the development of PCOS (9, 16), either directly through a GH-mediated or insulin-like growth factor effect on the ovaries (9, 17) or indirectly through associated insulin resistance (17, 18, 19, 20). Acromegaly induces hyperinsulinemia and an insulin-resistant state (21), and excessive GH levels can increase androgen secretion (13, 22, 23), whereas the severity of the clinical expression of PCOS is affected by both the degree of hyperandrogenism and insulin resistance (24). Thus, excessive GH levels, androgen secretion, insulin resistance, and PCOS seem to be interrelated.

An important observation of our study is the presence of reduced SHBG levels and the inverse association of SHBG with GH; this may explain the pathogenesis of menstrual irregularity in some patients with acromegaly despite normal testosterone levels. Total serum testosterone was not raised in our group of patients, but the preservation of testosterone levels seen even in amenorrheic women with impaired pituitary function, associated with low SHBG levels, could lead to increased androgen bioavailability (14, 15) and may thus account for the high prevalence of hirsutism also previously described in acromegalic women (1). Low levels of SHBG have been noted previously in acromegaly in general (25, 26), but they were not related to the estrogen status of these women. This is important, as patients with amenorrhea are estrogen deficient, and this alone might explain the low SHBG levels (27). In our study we noted the independent inverse correlation of GH with SHBG even in the estrogen-sufficient patients and the absence of intercorrelations among GH, E2, T4, and PRL, suggesting that GH per se resulted in a lowering of SHBG with preservation of total testosterone levels. Such an effect could either represent a direct effect of GH on SHBG or be indirect through raised insulin levels. Insulin and hyperinsulinemia are more important than estrogens in modulating the production of SHBG and therefore androgen clearance (14, 28, 29). This is particularly important, as neither estrogen deficiency alone (30) nor the type of obesity in acromegaly (31, 32) can account for the low SHBG levels observed; in addition, there was no alteration of thyroid status, another SHBG modulator (29). We, therefore, suggest that mechanisms other than gonadotropin deficiency or hyperprolactinemia alone may be involved in the pathogenesis of menstrual irregularity in some acromegalic women, especially in those who are estrogen sufficient. Acromegaly induces insulin resistance (21, 33, 34), which increases ovarian androgen production (35) and can affect ovarian function and menstrual cyclicity (15, 36), whereas a direct effect of GH/insulin-like growth factor I on steroid production and ovarian function has also been demonstrated (9, 17, 37). These mechanisms can operate either alone or in association, and we suggest that they could be responsible for the menstrual irregularity and clinical stigmata of PCOS seen in some acromegalic women with smaller tumors.

In summary, our series of acromegalic women presenting in the reproductive age range demonstrated a variety of menstrual abnormalities. Those with amenorrhea had larger tumors, and partial or complete gonadotropin deficiency, and a higher proportion had PRL levels above 1000 mU/L and impairment of anterior pituitary function compared to patients with normal cycles. Thus, partial or complete gonadotropin deficiency with or without concomitant hyperprolactinemia appears to be the major cause of the menstrual abnormality in this group. However, some women with oligomenorrhea and also those with regular cycles showed many of the clinical and biochemical characteristics of PCOS. The elevated GH levels per se are responsible for the high prevalence of signs of hyperandrogenism in women with acromegaly, either directly or via the effects of the induced hyperinsulinemia leading to reduced SHBG levels. This, in turn, may lead to menstrual abnormalities in some patients, especially those presenting with symptoms or signs of hyperandrogenism in an estrogen-sufficient state.

Received November 19, 1998.

Revised February 12, 1999.

Revised April 2, 1999.

Accepted April 13, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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