Pituitary neuroendocrine tumors (PitNET)-related menses peculiarities

1. Introduction

Prolactinomas are interesting pituitary neuroendo­crine tumors (PitNET) that develop from cells that produce prolactin, which results in tumor-related hyperprolactinemia⁽¹⁾. Of all pituitary tumors, 30-50% are represented by prolactinomas which usually affect women between the ages of 20 and 50 years old⁽²⁾. Prolactin is primarily stimulated by thyrotropin-releasing hormone (TRH) and estrogen, and inhibited by hypothalamic dopamine⁽³⁾. Prolactin directly suppresses kisspeptin production that lowers gonadotropin-releasing hormone (GnRH) activation and gonadotropins secretion, therefore promoting hypogonadism and infertility at the central level, that impacts reproductive axis modulation^(4,5).

Hyperprolactinemia is among the most common causes of hypogonadotropic hypogonadism, resulting in the manifestation of infertility, amenorrhea, galactorrhea, vaginal dryness, irritability, depression and osteoporosis/osteopenia. Infertility is caused by hyperprolactinemia in 2-4% of males and 7-20% of women⁽⁶⁾. The hormonal examination of reproductive dysfunction symptoms such as menstrual disturbance, amenorrhea and galactorrhea in females may lead to the diagnosis of prolactinoma⁽⁷⁾. Recovering gonadal function, decreasing tumor size, and returning prolactin to normalcy are the objectives of prolactinoma treatment⁽⁸⁾. Dopamine agonists, particularly cabergoline (which is the modern approach in this area rather than bromocriptine), are the preferred treatment for prolactinomas because they can finally cure, induce disease control, and restore fertility in both sexes⁽⁹⁾. Following the cabergoline treatment, it has been demonstrated that 82%, 53%, 86% and 67% of women with prolactinomas notice improvements in their amenorrhea, infertility, galactorrhea and sexual dysfunction, respectively⁽¹⁰⁾.

2. Materials and method

We aim to introduce a challenging case of PitNET-related menstrual cycle anomalies across a case study type of report. The data were collected retrospectively, and the patient agreed for the anonymous use of her medical history amid hospitalization. The parameters that are provided stand from a multidisciplinary perspective, including specific hormonal panel.

3. Results: case-focused presentation

3.1. Admission and medical history

A 40-year-old female was referred in April 2018 for secondary amenorrhea over the last four months. Personal and family history was unremarkable at that point. Menarche had occurred at 14 years old, and she had regular menses at 28-day intervals, lasting for five days. For almost a year, from February to October 2017, she used oral contraceptives for birth control. Following this, she experienced two sporadic menses before her menses ended in December 2017. She hadn’t been pregnant at all since menarche.

She denied experiencing any other symptoms sugges­tive of hypopituitarism, she did not report visual complaints, headaches or galactorrhea, and she was not taking any medication at the point of mentioned admission. She had a normal Body Mass Index of 24.22 kg/m (height 1.7 m and weight 70 kg). Blood pressure was 120/80 mmHg. Thyroid clinical exam was within normal limits.

3.2. Laboratory findings

Baseline biochemistry kit was normal. The initial hormonal assessments showed a high prolactin level of 177.3 ng/mL (normal range between 4.79 and 23.3 ng/mL), low estradiol levels of 8.77 pg/mL (normal range between 12.4 and 233 pg/mL for menstruating females), FSH (follicle-stimulanting hormone) of 8.56 mUI/mL (normal range: 3.5-12.5 mUI/mL), and LH (luteinizing hormone) of 10.19 mUI/mL (normal range between 2.4 and 12.6 mUI/mL). While no symptoms of other pituitary hormonal dysfunction were obvious, the assays showed: IGF-1 (insulin-like growth factor) of 276.7 ng/mL (normal range between 81 and 278 ng/mL), ACTH (adrenocorticotropic hormone) of 23.9 pg/mL (normal range between 3 and 66 pg/mL), and TSH (thyroid-stimulating hormone) of 1.92 µUI/mL (normal range: 0.4-4.5). The oral glucose tolerance test (OGTT) revealed no growth hormone (GH) oversecretion, according to a GH nadir below 0.4 ng/mL.

3.3. Imaging assessment and further evaluation

An initial computed tomography scan of the pituitary gland revealed a heterogeneous mass in the pituitary re­gion, the mean size of the lesion being 8 by 5 mm, consistent with the diagnosis of a microadenoma. Other possible causes of hyperprolactinemia were not identified. The gynecological evaluation was within normal limits; the pregnancy test results were negative. An intact visual field and good acuity were found during the ophthalmological examination, and the cardiologic examination was normal.

3.4. Outcome

Based on the clinical presentation and the test results, the patient was diagnosed with macroprolactinoma, and she was prescribed cabergoline 3 mg/twice weekly. However, at subsequent follow-ups, prolactin decreased to the level of 11.84 ng/mL (normal range between 4.79 and 23.3 ng/mL) after four months. The positive effect on menses was observed after more than four months and remained regular under medication. Moreover, it was confirmed a reestablish of the gonadal function, with estradiol concentration of 61.29 pg/mL (normal range between 12.4 and 233 pg/mL), FSH of 9.61 mUI/mL (normal range between 3.5 and 12.5 mUI/mL), and LH of 4.6 mUI/mL (normal range between 2.4 and 12.6 mUI/mL) within the follicular phase of the menstrual cycle. Over the time, prolactin remained normal, and the tumor’s size was declining, but not more than 50%; in the light of this, the therapy was continued for five more years. The prolactin levels during the treatment are present in Figure 1.
 

Additionally, the patient’s IGF-1 was at the upper limit of normal at the follow-up. There was no GH secretion detected by the OGTT, including repeated values over time. In August 2023, she had regular menses at 28-day intervals, lasting for five days, and no other complaints under weekly 0.5 mg of cabergoline. The laboratory values (Table 1) and the hormonal testing (Table 2) indicated normal prolactin levels of 12.23 ng/mL (normal range between 3.34 and 26.72 ng/mL), and a stationary pituitary tumor was revealed by a computed tomography scan, of 6.2 by 2.7 mm. Despite recommendations of continuing with a low dose of cabergoline, the subject’s decision was to stop it. Yet, lifelong surveillance is mandatory and, in case the lady intends to conceive in her 40s, a re-starting of the dopamine agonist is most likely needed. 
 

4. Discussion

4.1. Prolactin role with respect to menstrual cycle

There is clear evidence linking hyperprolactinemia to irregular menstruation. The suppression of the pulsatile GnRH is the mechanism proposed for amenorrhea. Raising the prolactin level suppresses LH from being secreted and inhibits ovulation during the menstrual cycle⁽¹¹⁾. Furthermore, an inadequate luteal phase can lead to infertility, even in cases where menstruation is normal, likewise in those who were infertile, but had normal menstruation and hyperprolactinemia⁽¹²⁾. In women with hyperprolactinemia, various manifestations of menstrual disorders have been observed, including oligomenorrhea, bleeding between cycles, polymenorrhea and hypermenorrhea⁽¹³⁾.

Additionally, it has been observed that, paradoxically, IGF-1 concentrations may rise with long-term cabergoline therapy in some female patients⁽¹⁴⁾. Suppression of prolactin secretion by cabergoline might likely allow hormone hypersecretion from GH-secreting cells that do not respond to cabergoline⁽¹⁵⁾. Hence, there is an ongoing debate on how long-term cabergoline therapy impacts serum IGF-1 levels in patients confirmed with this type of PitNETs⁽¹⁶⁾. Other endocrine tumors and autoimmune conditions, besides GH producing PitNETs, might also influence the levels of IGF-1 and prolactin^(17-19).

4.2. Drug interferences with prolactin levels

In this case, the patient used oral contraceptives before the actual diagnosis of a prolactinoma. Whether this is prone in masking a prolactinoma, it is a matter of debate and, once the confirmation of a prolactin secreting PitNET is done, the use of estroprogestives is no longer recommended^(20,21). On the other hand, noncompliance to dopamine analogues, as it was finally registered in this case, might bring not only an increased prolactin and a tumor growth, but also long-term negative effects of untreated early hypogonadism. Of note, apart from glucocorticoids exposure and primary hyperparathyroidism, this stands for a most common cause of trabecular bone score and bone mineral density deterioration^(22,23). Notably, the patient was also followed amid the years of COVID-19 pandemic whereas compliance to long standing strategies in the field of endocrine and nonendocrine conditions had been affected^(24,25). Alternatively, young patients with prolactinomas who are candidates to lifelong medical therapy might undergo surgery for PitNET, including in individuals who develop a lack of adherence in taking cabergoline for years, apart from the cases with macroadenomas that display local compressive effects^(26,27).

5. Conclusions

Secondary amenorrhea represents a common element that is found during the evaluation done by endocrinologists and obstetricians/gynecologists. Hyperprolactinemia should be taken into consideration as an alternative differential diagnosis. The treatment of this disorder can be essential for these women to have regular menses.  

 Abbreviations: ACTH = adrenocorticotropic hormone; GnRH = gonadotropin-releasing hormone; GH = growth hormone; FSH = follicle-stimulating hormone; IGF-1 = insulin-like growth factor-1; LH = luteinizing hormone; OGTT = oral glucose tolerance test; PitNET = pituitary neuroendocrine tumors; TRH = thyrotropin-releasing hormone

 Corresponding author: Claudiu Nistor, e-mail: ncd58@yahoo.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.