Prolactinomas in Male and Female Patients: A Comparative Clinicopathologic Study

doi:10.4065/73.11.1046

Mayo Clinic Proceedings

Volume 73, Issue 11, November 1998, Pages 1046-1052

https://doi.org/10.4065/73.11.1046 Get rights and content

Objective

To explore the basis of the gender-based differences in endocrine and surgical findings in patients with prolactinoma (prolactin cell adenoma) as well as in their clinical outcome.

Material and Methods

In young or reproductive-age female patients, older women (beyond 40 years of age), and male patients, we systematically studied the following factors: operative and endocrine features (tumor size, invasiveness, preoperative serum prolactin level, and biochemical outcome), specific biologic variables (mitotic index, MIB-l labeling index, and p27 immunoreactivity), and hormone receptor status (estrogen and progesterone receptor proteins as well as dopamine D₂ receptor messenger RNA).

Results

Of the various factors assessed, the preoperative prolactin level and MIB-l labeling index were lower in young female patients in comparison with older female and particularly male patients. Hormone levels were also positively associated with mitotic activity as well as the MIB-l labeling index. Although invasion was infrequent in microadenomas of young female patients, no statistically significant differences in tumor size or invasiveness were noted among the three patient groups. Absence of differences in invasiveness may, in part, be explained by artifacts of case selection.

Conclusion

The basis for the observed differences in proliferative activities in tumors of the three study groups is not readily apparent but may reflect differences in the endocrine milieu or the effect of sex steroid hormone receptors, tumoral vascularity, or specific growth factors.

Section snippets

Study Group

We retrieved 72 cases of prolactinoma from the files of the Mayo Clinic Tissue Registry. Patients were randomly selected on the basis of age and included young (reproductive-age) women, older women (beyond 40 years), and male patients of similar age ranges. All patients had undergone operative treatment during the years 1963 through 1991; none had previously been treated with dopamine agonists. Case selection and, as a result, case numbers were limited by availability of adequate

Clinical, Operative, and Endocrine Data

Stratified by age and sex, the study population consisted of 38 young (reproductive-age) female patients defined as ranging in age from 20 to 40 years (mean, 27), 14 older female patients ranging from 42 to 68 years of age (mean, 49), and 20 male patients from 20 to 66 years of age (mean, 40).

As indicated in Table 1, the prevalence of macroadenomas was higher in male patients (15 of 20 or 75%) than in older female patients (8 of 14 or 57%) or young female patients (19 of 38 or 50%). These

DISCUSSION

Clinically, prolactinomas display gender-based differences in biologic behavior, particularly between young female and male patients. The current study of the endocrine, operative, and pathologic features of prolactinomas in young and older female patients as well as in male patients was undertaken in an effort to gain insight into these differences.

The study demonstrated that proliferative activity, as reflected by mitotic counts (P = 0.0001) and MIB-1 labeling indices, was significantly

CONCLUSION

Because the current study indicates that prolactinomas in male and older female patients have higher MIB-1 labeling indices than do those of young female patients, we conclude that in female patients the endocrine milieu or reproductive status may affect the proliferative activity of their prolactinomas. Furthermore, MIB-1 labeling indices and mitotic counts apparently are similar in prolactinomas of male and older female patients. Interestingly, differences in tumor size, frequency of

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Cited by (93)

Prevalence of Hyperprolactinemia and Clinically Apparent Prolactinomas in Men Undergoing Fertility Evaluation
2022, Urology
Citation Excerpt :
These tumors tend to be macroadenomas and can be more invasive and proliferative, and since they are frequently detected late, local mass effects such as headaches, visual field defects and cranial nerve deficits are the common presenting features.9,11,12,21 While the natural history of these tumors is not fully understood, it is possible that symptomatic macroadenomas in men result from the slow and steady growth of microadenomas.11,22,23 Fertility evaluation in younger men provides clinicians with the opportunity to detect prolactinomas at an earlier stage, thereby sparing the morbidity of more advanced tumors.
To determine prevalence of hyperprolactinemia and prolactinoma among men presenting for initial fertility evaluation.
We performed a retrospective review of men presenting for initial fertility evaluation at a tertiary care, academic health system between 1999 and 2018. Men with measured prolactin levels were analyzed to determine prevalence of hyperprolactinemia and prolactinoma. We compared clinical characteristics of men with and without hyperprolactinemia. Univariable and multivariable analysis were used to determine factors associated with hyperprolactinemia. We assessed effects of hyperprolactinemia and prolactinoma on testosterone levels, semen parameters and pregnancy outcomes after treatment.
A total of 3101 men had serum prolactin level measured. 65 (2.1%) had hyperprolactinemia. Patients with hyperprolactinemia had lower testosterone (median 280 ng/dL vs 313 ng/dL, P = 0.038) and lower total motile sperm count (median 7.0 million vs 34.7 million, P = 0.001) compared to men without hyperprolactinemia. 43.1% of men with hyperprolactinemia had oligospermia vs 21.5% of men without hyperprolactinemia (P<0.001). Univariable analysis demonstrated that men with elevated luteinizing hormone (LH) (OR 1.077, P = 0.001) and follicle-stimulating hormone (FSH) (OR 1.032, P = 0.002) were more likely to have hyperprolactinemia. Men with oligospermia were more likely to have hyperprolactinemia (OR 2.334, P = 0.004). On multivariable analysis, neither hormone parameters nor oligospermia were associated with elevated prolactin (P>0.05). Of the 65 men with hyperprolactinemia, 11 (17%) were diagnosed with a prolactinoma, resulting in an overall prevalence of 11 in 3101 (0.35%).
The overall prevalence of prolactinoma in our cohort of men undergoing fertility evaluation was 35-fold higher than the prevalence in the general male population.
Prolactinomas
2021, Presse Medicale
Citation Excerpt :
Familial syndromes were found in 5% of the 262 patients and 3% of the 65 prolactinoma patients [40]. MEN-1 is caused by mutation in the MEN1 gene located on chromosome 11q13, that encodes the protein Menin, and 22% of patients develop prolactinoma, that are generally large, with invasive behavior and resistant to conventional treatment [42,43]. MEN-4 presents with the same phenotype, but mutations are found in the CDKN1B gene, located on chromosome 12p13 [44].
Hyperprolactinemia, defined by a level of serum prolactin above the standard upper limit of normal range, is a common finding in clinical practice and prolactinomas are the main pathological cause. Prolactinomas lead to signs and symptoms of hormone oversecretion, such as galactorrhea and hypogonadism, as well as symptoms of mass effect, including visual impairment, headaches and intracranial hypertension. Diagnosis involves prolactin measurement and sellar imaging, but several pitfalls are involved in this evaluation, which may difficult the proper management. Treatment is medical in the majority of cases, consisting of dopamine agonists, which present high response rates, with a very favorable safety profile. Major adverse effects that should be monitored consist of cardiac valvulopathy and impulse control disorders. Other treatment options include surgery and radiotherapy. Temozolomide may be used for aggressive or malignant carcinomas. Finally, pregnancy outcomes are similar to general population even when dopamine agonist treatment is maintained.
Physiologic and Pathophysiologic Alterations of the Neuroendocrine Components of the Reproductive Axis
2019, Yen & Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management: Eighth Edition
The neurohormonal control of reproduction involves a network of central and peripheral signals in the hypothalamic-pituitary-gonadal axis. The gonadotropin-releasing hormone (GnRH) system plays a crucial part in this axis.
Integration of multiple signals ultimately results in neuronal release of GnRH, which then travels via the hypothalamic–hypophyseal portal circulation to the anterior pituitary gland, where it binds to the GnRH receptor 1 and upregulates synthesis and secretion of two pituitary hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). GnRH secretion is pulsatile with discrete bursts of GnRH affecting the release of pulses of LH and FSH by the pituitary. This chapter describes medical conditions as well as endogenous and exogenous factors that result in abnormalities of this complex hypothalamic-pituitary axis.
Hypopituitarism patterns among adult males with prolactinomas
2016, Clinical Neurology and Neurosurgery
Citation Excerpt :
Symptoms caused by hyperprolactinemia are often underestimated by the majority of male patients with prolactinomas. Delays in diagnosis may account for the greater incidence of macroadenomas with visual field defects and hypopituitarism at first presentation among men than women [13]. In fact, over half of the male patients with prolactinomas complained of impaired vision with/without headache, whereas sexual dysfunction was often found based on disease history and physical examination.
The objective of this study was to characterize hypopituitarism in adult males with prolactinomas.
We retrospectively analyzed the records of 102 consecutive patients, classified under three categories based on adenoma size at diagnosis: 1.0–2.0 cm (group A), 2.1–4.0 cm (group B), and >4.0 cm (group C). Further, 76 patients had successful outcomes at follow-up. We compared different forms of pituitary hormone dysfunction (growth hormone deficiency, hypogonadism, hypothyroidism, and hypocortisolism) based on the maximal adenoma diameter.
Serum prolactin levels were significantly correlated with the maximal adenoma diameter (r = 0.867; P = 0.000). Of the patients, 89.2% presented with pituitary failure, which included 74.5% with growth hormone deficiency, 71.6% with hypogonadism, 28.4% with hypothyroidism, and 12.7% with hypocortisolism. The three groups did not differ significantly (P > 0.05) in the incidence of hypopituitarism, including the extent of pituitary axis deficiency, at presentation and following treatment. However, there was a statistically significant difference in the degree of hypogonadism in cases of acquired pituitary insufficiency at diagnosis (P = 0.000).
In adult males with prolactin-secreting adenomas, the most common form of pituitary hormone dysfunction was growth hormone deficiency and hypogonadism, whereas hypocortisolism was less common. The maximal adenoma diameter and prolactin secretion did not determine hormone insufficiency in adult males with prolactinomas, but these factors did affect the degree of both hypogonadism and hypothyroidism. Smaller tumors were found to recur more frequently than large tumors, and recovery was more common in cases of growth hormone deficiency and hypogonadism.
Suppression of MMQ cells by fulvestrant: Possible mechanism of action and potential application for bromocriptine-resistant prolactinomas
2013, Journal of Clinical Neuroscience
Citation Excerpt :
The PRL level was higher in males than in females, and the tumor volume was larger in males than in females. This finding is consistent with a report that demonstrated that the PRL level in male patients was significantly higher than that in young female patients.23 Our results and those previously published may reflect that hyperprolactinemia induces amenorrhea, galactorrhea and infertility in females, allowing earlier tumor diagnosis.
Bromocriptine is an effective treatment for most prolactinomas. Estrogen receptor (ER) antagonists are an alternative for treating patients with bromocriptine-resistant prolactinomas (BCRP). Previously, we reported that fulvestrant, a selective ER antagonist, significantly inhibited the proliferation of, and prolactin secretion by, MMQ cells, a prolactin-secreting rat pituitary cell line, an exemplary model for prolactinoma. In this study, we used fulvestrant to block ERα expression by MMQ cells and analyzed the expression of β-catenin and Wnt inhibitory factor-1 (WIF1) to investigate the effects of fulvestrant on the Wnt signaling pathway. In addition, we examined the gene expression of ERα, β-catenin and WIF1 in clinical BCRP specimens to explore the correlation between gender and clinical features. There was no significant difference in β-catenin expression between fulvestrant-treated cells and untreated cells, whereas WIF1 expression was higher in the treated cells. In clinical BCRP specimens, ERα expression was higher (especially in male patients), whereas β-catenin expression was similar to normal pituitaries. In addition, WIF1 expression was significantly lower in BCRP specimens than in normal pituitaries. The tumor volume was larger in male patients than in female patients. Prolactin concentration was positively correlated with tumor volume, and a positive linear correlation was observed between ERα expression and tumor volume. In conclusion, the anti-tumor activity of fulvestrant on MMQ cells seems to be associated with ERα and the non-canonical Wnt pathway, and higher ERα levels in male patients with BCRP may contribute to the larger tumor volumes observed. Fulvestrant holds promise as a therapeutic agent for BCRP.
CSF Rhinorrhea: An Early Complication of Dopamine-Sensitive Macroprolactinoma
2017, AACE Clinical Case Reports
Citation Excerpt :
The larger tumor size in men presumably results from a diagnostic delay, as menstrual abnormalities are often the presenting symptom in women, thus prompting more timely evaluation. Gender-specific differences in tumor biology may play a role, but this remains unclear (4). Most (~60%) adult men with macroprolactinomas are diagnosed before the age of 40 years, mainly in the fourth decade of life (1).
Objective: Cerebral spinal fluid (CSF) leak is a known surgical complication of invasive macroprolactinomas. Case reports suggest this complication can occur with dopamine agonist treatment alone.
Methods: We present clinical features, imaging, and biochemical characteristics of one such case of an invasive macroprolactinoma complicated with early CSF leak.
Results: A 35-year-old obese male presented with weight gain of over 100 pounds within the last year and absent morning tumescence. Laboratory evaluation was notable for elevated total prolactin (PRL) (4,655 ng/mL) and low total testosterone (24 ng/dL). Magnetic resonance imaging (MRI) revealed a large pituitary adenoma (4.2 × 2.5 × 3.5 cm) extending into the cavernous and sphenoid sinuses, partially eroding the sphenoid bone. Dopamine agonist, cabergoline 250 μg twice/week was started. After two doses, the patient developed CSF rhinorrhea and was hospitalized. Adenoma was smaller in size (4.1 × 1.9 × 3.3 cm), and total PRL declined to 824 ng/mL. An endoscopic subtotal resection of adenoma with CSF leak repair was performed. Treatment with cabergoline was continued, resulting in complete resolution of CSF leak within a few days. Two months later, cabergoline dose was increased to 500 μg twice a week as adenoma size remained unchanged. One month later, MRI showed regression of the pituitary tumor with cystic changes. Serum PRL level substantially declined (total PRL, 102 ng/mL).
Conclusion: Clinicians should be highly observant of and educate patients about CSF rhinorrhea as potential early consequence of medical therapy of macroprolactinoma to avoid misdiagnosis and fatal sequelae of this complication.
Abbreviations: CSF cerebral spinal fluid; DA dopamine agonist; MRI magnetic resonance imaging; PRL prolactin

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Original ArticleProlactinomas in Male and Female Patients: A Comparative Clinicopathologic Study

Objective

Material and Methods

Results

Conclusion

Section snippets

Study Group

Clinical, Operative, and Endocrine Data

DISCUSSION

CONCLUSION

Endocrinol Metab Clin North Am

Fertil Steril

Mayo Clin Proc

Cell

Lancet

Regional neuropathology: hypothalamus and pituitary

Tumors of the pituitary gland

Surgical pathology of the pituitary: the adenomas

Parti Pathol Annu

Pituitary prolactinomas

Clin Endocrinol

Prolaclin-secreting pituitary tumors in amenorrheic women: a comprehensive study

Endocr Rev