A Comparative Case Study of Pituitary Macroadenoma Treatment: No Intervention, Medication, Nutrition, and Endoscopic Transsphenoidal Surgery

doi:10.21203/rs.3.rs-5252942/v1

This paper presents a detailed case report of a 19-year-old woman diagnosed with hyperprolactinemia, followed over a six-year period until her full recovery at age 25. The patient’s initial complaint of ineffective laser hair removal led to the discovery of elevated prolactin levels, followed by a diagnosis of polycystic ovary syndrome (PCOS). Despite undergoing multiple pharmacological treatments, including Bromocriptine and Cabergoline, the patient developed secondary amenorrhea and was diagnosed with a treatment-resistant pituitary macroadenoma. Dietary modifications and herbal supplements provided only temporary relief. Ultimately, surgical intervention via endoscopic transsphenoidal surgery successfully resolved the patient’s condition, with normalized prolactin levels and the resolution of amenorrhea. This case highlights the challenges of managing treatment-resistant hyperprolactinemia and underscores the importance of adaptable treatment plans and the potential necessity of surgery.

Hyperprolactinemia

Prolactinoma

Pituitary Macroadenoma

PCOS

Dopamine Agonists

Bromocriptine

Cabergoline

Secondary Amenorrhea

Endoscopic Transsphenoidal Surgery

Treatment-Resistant

This study presents a comprehensive case report of a 19-year-old woman diagnosed with hyperprolactinemia and followed over a six-year period until her full recovery at age 25. The patient initially sought medical attention due to unsatisfactory results from laser hair removal treatment, despite having a regular menstrual cycle. Subsequent hormonal testing revealed elevated prolactin levels, leading to a diagnosis of hyperprolactinemia and polycystic ovary syndrome (PCOS).

Hyperprolactinemia is a condition characterized by excessive production of prolactin, a hormone primarily responsible for milk production in mammals [1]. While it is normal for prolactin levels to increase during pregnancy and breastfeeding, elevated levels in other circumstances can lead to various reproductive and metabolic disturbances [2]. In this case, the patient's journey from diagnosis through various treatment modalities to eventual surgical intervention provides valuable insights into the management of persistent hyperprolactinemia [3].

The study details the patient's response to different pharmacological interventions, including Bromocriptine and Cabergoline, as well as dietary modifications and herbal supplements [4]. Despite these treatments, the patient developed secondary amenorrhea and was ultimately diagnosed with pituitary macroadenoma [5]. The case highlights the challenges in managing prolactinomas resistant to medical therapy and underscores the importance of continuous monitoring and adaptable treatment strategies [6].

This report aims to contribute to the existing literature on hyperprolactinemia management by providing a detailed account of treatment responses, hormonal fluctuations, and the eventual surgical outcome [7]. The findings may offer valuable insights for clinicians dealing with similar cases of treatment-resistant prolactinomas and emphasize the potential need for surgical intervention in certain cases of hyperprolactinemia [7].

A. Literature Review

Hyperprolactinemia is a common endocrine disorder characterized by elevated levels of prolactin in the blood [8]. It affects both men and women, though it is more prevalent in women of reproductive age [9]. The condition can arise from various causes, including physiological states like pregnancy and breastfeeding, as well as pathological conditions such as pituitary tumors, particularly prolactinomas [10]. Prolactinomas are the most common type of functioning pituitary adenomas, accounting for approximately 40% of all pituitary tumors [11]. These benign tumors secrete excess prolactin, leading to a range of symptoms including menstrual irregularities, galactorrhea, infertility, and sexual dysfunction [12].

The diagnosis of hyperprolactinemia typically involves serum prolactin measurement and imaging studies. Magnetic Resonance Imaging (MRI) is the gold standard for visualizing pituitary tumors due to its superior soft tissue contrast and ability to detect small lesions[13].

The first-line treatment for prolactinomas is typically dopamine agonist therapy. Bromocriptine and cabergoline are the most commonly used medications, with cabergoline often preferred due to its higher efficacy and better tolerability profile [14]. In the present case, the patient was initially treated with bromocriptine followed by various regimens of cabergoline. This approach aligns with standard practice, as studies have shown that dopamine agonists can effectively reduce prolactin levels and shrink tumor size in most patients with prolactinomas [15]. While there is limited scientific evidence supporting the efficacy of these specific interventions for hyperprolactinemia, some studies have suggested that certain dietary factors may influence prolactin levels [16], [17].

For patients with prolactinomas resistant to medical therapy or those with large tumors causing compressive symptoms, surgical intervention may be necessary [18]. The endoscopic transsphenoidal approach, as used in this case, has become the preferred surgical method due to its minimally invasive nature and improved visualization [19]. None of the existing research has utilized a comprehensive approach, including long-term follow-up and a variety of diagnostic and treatment methods, to determine the most impactful approaches for prolactinomas.

A. Participant

We monitored a 19-year-old woman from the onset of her condition until her full recovery at the age of 25. A 19-year-old female patient, who experienced inadequate results from laser hair removal treatment despite maintaining a regular menstrual cycle averaging 35 days, underwent hormonal testing that revealed elevated prolactin levels.

B. Treatment Features and Timeline in Managing Hyperprolactinemia

Prolactin levels were monitored in the patient over a six-year period, during which various therapeutic interventions were implemented. The treatment began with Bromocriptine (2.5 mg per day) for three months, followed by a two-year period without pharmacological intervention. Subsequently, a series of Cabergoline (Dostinex) regimens were administered: 0.5 mg per week for three months, then 1 mg per week combined with Vitagnus for one month. For one month, the patient was administered Vitagnus, a herbal supplement derived from Vitex agnus-castus, in accordance with the prescribed instructions. The treatment regimen included 30 to 40 drops of the liquid form in water each morning on an empty stomach.

This was adjusted to 1 mg per week of Cabergoline alone for 23 months. The dosage was then increased to 2 mg per week, combined with a raw vegan diet for three months, during which an MRI was performed. The same dosage was maintained for an additional three months, supplemented with a vegan diet, royal jelly, and pine nuts. Following this, the Cabergoline dose was increased to 3 mg per week with a return to a normal diet for two months, accompanied by another MRI. This regimen continued for 4 months, during which an additional MRI was conducted, and the dosing frequency was adjusted from three to six pills per week. After these pharmacological interventions, the patient underwent surgical treatment in Fig. 1 and we had the last MRI prior to surgery.

Serum prolactin levels were measured using a chemiluminescence immunoassay (CLIA) method. Blood samples were collected from patients in the morning, between 7:00 and 9:00 AM, after an overnight fast and approximately one hour after waking. Patients were instructed to rest for 30 minutes before sample collection to minimize stress-induced prolactin elevation. Then, all levels were normalized by Eq. 1.

Equation 1

$$\:Nor\_Prolacti{n}_{level}=\frac{Prolacti{n}_{level}}{Maximum\:of\:Normal\:Thereshold\:}$$

We also monitored additional blood parameters at specific intervals, including AMH, T4, TSH, LH, FSH, estradiol, morning cortisol, IGF-1, and menstrual cycle patterns.

MRI scans were performed on the patient using a high-field MRI system, focusing on the sellar region and surrounding structures. The imaging protocol included T1-weighted, T2-weighted, and FLAIR sequences to evaluate any masses or lesions. The scans assessed signal characteristics and relationships with adjacent vascular structures, particularly around the sella. Additionally, gray and white matter integrity in the cerebral hemispheres was evaluated, along with the cerebellum and brain stem. Ventricular size and configuration were also examined to rule out midline shift, and bony structures were assessed for integrity.

Following surgery, a histopathological examination was conducted. The excised tissue was preserved in formalin and subsequently processed for microscopic evaluation to confirm the diagnosis and assess tumor characteristics.

B.1 Endoscopic Transsphenoidal Surgery

In this study, pituitary macroadenomas were surgically removed using Endoscopic Transsphenoidal Surgery, a technique that minimizes disruption to surrounding brain tissue and enhances tumor visualization for effective resection. The procedure was conducted under general anesthesia, with careful monitoring and control of intraoperative noise levels to reduce stress on the surgical team and improve focus. Sound-absorbing materials were utilized in the operating room to diminish ambient noise, and communication among team members was kept concise and directed. Postoperatively, patients were evaluated for complications related to hormone levels and neurological function, with meticulous monitoring of the surgical site to ensure optimal recovery. This methodological approach highlights the significance of maintaining a controlled auditory environment in achieving successful surgical.

A. Initial Condition

The initial normalized prolactin level ($\:Nor\_Prolacti{n}_{level}$) was 4.622 (NO: 0). The patient experienced menstrual cycles averaging 4 days in duration, with intervals of approximately 40 days. She was diagnosed with Polycystic Ovary Syndrome (PCOS).

B. Treatment Response on Prolactin Level

Other tests, including Fasting Blood Sugar, Blood Urea Nitrogen, Creatinine, CRP, TSH, T3, T4, Estradiol, Cortisol AM, ACTH AM, and IGF-1, were all within normal ranges during the study. The average FSH level was 1 mIU/mL, and the average LH level was 0.1 mIU/mL, both of which are considered low.

In Fig. 2 and Table 1 present data related to a patient's prolactin levels and various treatments. The initial prolactin level was notably elevated at 4.622, far above the normal range of 0 to 1. Following treatment with Bromocriptine (17.5 mg/week) for three months, prolactin levels were reduced to 1.48, although the patient was diagnosed with PCOS. After stopping treatment for 24 months, prolactin levels rose to 1.8, and secondary amenorrhea developed after 15 months. Cabergoline interventions were then administered at doses ranging from 0.5 mg/week to 3 mg/week, with varied durations. Despite treatment, prolactin levels remained elevated, fluctuating between 1.09 and 3.2, with the patient continuing to experience secondary amenorrhea throughout. The treatment doses were adjusted, but normalized prolactin levels (0 to 1) were never fully achieved. The patient's diet, including raw-vegan and vegan variations, also played a role in the management, yet the prolactin levels remained above normal. There was no significant change in prolactin levels with either high or low drug doses, indicating that the macroadenoma's behavior was independent of the dosage administered.

The raw and vegan diet temporarily lowered prolactin levels, bringing them close to the normal range, but the effect was short-lived.

Table 1

Treatment Response on Prolactin Level
NO	Treatment	Duration	$\:\mathbf{N}\mathbf{o}\mathbf{r}\mathbf{m}\mathbf{a}\mathbf{l}\mathbf{i}\mathbf{z}\mathbf{e}\mathbf{d}$$\:\mathbf{p}\mathbf{r}\mathbf{o}\mathbf{l}\mathbf{a}\mathbf{c}\mathbf{t}\mathbf{i}\mathbf{n}$	Comments
0	-	-	4.622	Initial value
1	Bromocriptine Treatment 17.5 mg/week	3 months	1.48	PCOS
2	No drug	24 months	1.8	Secondary Amenorrhea after 15-months
3	Cabergoline Intervention 0.5 mg/week	3 months	1.62	Secondary Amenorrhea
4	Cabergoline Intervention 1 mg/week	21 months	1.94	Secondary Amenorrhea
5	Cabergoline Intervention 1 mg/week	3 months	2.38	Secondary Amenorrhea
6	Cabergoline Intervention 2 mg/week	3 months	1.988	Raw-Vegan Secondary Amenorrhea
7	Cabergoline Intervention 2 mg/week	1 month	1.09	Vegan Secondary Amenorrhea
8	Cabergoline Intervention 2 mg/week	1 month	1.25	Vegan Secondary Amenorrhea
9	Cabergoline Intervention 2 mg/week	1 month	2.89	Vegan Secondary Amenorrhea
10	Cabergoline Intervention 3 mg/week	1 month	3.2	Secondary Amenorrhea
11	Cabergoline Intervention 1.5 mg/week	1 month	3.12	Secondary Amenorrhea
12	Cabergoline Intervention 3 mg/week	3 months	2.11	Secondary Amenorrhea
13	Cabergoline Intervention 3 mg/week	1 months	2.22	Secondary Amenorrhea

C. Treatment Response on MRI images

Imaging reveals an enhancing sellar mass characterized by internal small cystic changes and avid enhancement. The mass exhibits isosignal on T1-weighted images and high signal on T2-weighted and FLAIR sequences. It is associated with a widened sellar region and demonstrates superior extension into the suprasellar space, leading to upward deviation of the optic chiasm and anterior cerebral arteries. The dimensions of the mass are approximately in Table 2. There is close contact between the mass and the bilateral internal carotid arteries, although no visible encasement is noted. A pituitary macroadenoma is suggested.

Table 2

Pituitary macroadenoma dimensions
Months after initial condition	Size
50 months	31x26x28 mm
55 months	30x28x26 mm
60 months	27x24x22 mm
66 months	27x24x26 mm

D. Surgical Outcomes

As macroadenoma does not respond to drugs, the subject went through Endoscopic Transsphenoidal Surgery. Two days after surgery the Normalized Prolactin level was 0.2. The histopathological examination reveals a benign pituitary adenoma characterized by prolactin-secreting cells (prolactinoma). The tumor is composed of uniform, densely packed cells with moderate cytoplasm and round to oval nuclei. No evidence of necrosis or significant mitotic activity is observed, consistent with a benign process.

E. Postoperative Monitoring

Two months after surgery, the Secondary Amenorrhea stopped. And the subject has 5 days of period with 37 days interval on average. After one year, the subject interval days between period has reduced to 30 days.

6 months after surgery the normalized prolactin level was 0.22 (NO: 14). 12 months after surgery the normalized prolactin level was 0.49 and the FSH was 2.3 which was normal (NO: 15).

F. Summary of Key Findings

Initial medication effectively reduced prolactin levels, but they subsequently rebounded. A raw vegan diet provided temporary relief. Increasing medication dosage did not significantly impact prolactin levels or tumor size. Surgical intervention was the only effective treatment. Prolactin levels may have begun to rise 15 months after diagnosis. FSH and LH levels improved markedly following surgery, and secondary amenorrhea resolved within two months. The unmentioned parameters were normal during study.

The presented case offers valuable insights into the complexities of managing hyperprolactinemia, particularly in cases involving pituitary macroadenomas resistant to pharmacological treatments. Over a six-year follow-up period, the patient underwent a range of medical interventions, including dopamine agonist therapy, lifestyle and dietary changes, and ultimately surgical intervention, providing a comprehensive view of therapeutic responses and long-term outcomes.

A. Pharmacological Management

The initial response to Bromocriptine and Cabergoline highlights the typical pharmacological approach for treating prolactinomas [20]. Cabergoline, known for its higher efficacy and better tolerability than Bromocriptine, was expected to reduce prolactin levels and shrink the tumor, as observed in many cases of prolactinoma management [21]. However, despite a gradual increase in the Cabergoline dosage and the integration of herbal supplements and dietary modifications, the patient's prolactin levels fluctuated, and the tumor size remained relatively unchanged. This lack of response underscores the complexity of managing prolactinomas resistant to standard medical therapy .

The case also emphasizes the potential role of diet in managing hyperprolactinemia. A raw vegan diet appeared to have a temporary effect on prolactin levels, suggesting that dietary modifications may influence hormonal regulation. While the exact mechanisms remain unclear, studies have hinted at the influence of certain dietary factors on prolactin secretion [22]. However, this effect was transient, and ultimately, medical treatment alone was insufficient to achieve long-term control of the patient’s condition.

B. Challenges in Persistent Hyperprolactinemia

One of the key challenges highlighted in this case is the persistence of hyperprolactinemia despite escalating pharmacological interventions. The gradual progression of the tumor and its resistance to dopamine agonist therapy necessitated continuous monitoring and adjustments to the treatment plan. The patient's development of secondary amenorrhea further complicated the management, indicating the systemic impact of persistent hyperprolactinemia on reproductive health [23], [24]. This aligns with existing literature, which describes menstrual irregularities as a common symptom of elevated prolactin levels [25].

C. Role of Surgery in Treatment-Resistant Prolactinomas

When prolactinomas do not respond adequately to medical therapy, surgical intervention becomes a critical consideration [26]. In this case, the endoscopic transsphenoidal surgery provided a successful outcome, as demonstrated by the immediate postoperative drop in prolactin levels and the resolution of secondary amenorrhea. The use of this minimally invasive approach has been increasingly favored in the treatment of pituitary tumors due to its precision, reduced morbidity, and shorter recovery time. The normalization of the patient’s hormonal profile post-surgery, including prolactin, FSH, and LH levels, further confirms the effectiveness of this intervention. Histopathological analysis confirmed the benign nature of the prolactinoma, consistent with most pituitary adenomas [11]. The resolution of the patient’s reproductive dysfunction following surgery emphasizes the critical role of surgical intervention in cases where medical management fails.

C, Clinical Implications

This case underscores the importance of individualized treatment plans for patients with hyperprolactinemia, particularly those with resistant prolactinomas. While dopamine agonists remain the first-line therapy, this case demonstrates that not all patients will respond favorably to pharmacological interventions alone. Continuous monitoring of prolactin levels, tumor size, and reproductive health is essential for timely adjustments in treatment strategy.

Moreover, this case highlights the potential need for early consideration of surgical intervention in prolactinomas resistant to medical therapy. Surgical removal of the tumor resulted in the patient’s full recovery, both hormonally and reproductively, demonstrating that surgery can provide definitive treatment when other modalities fail. For clinicians, this emphasizes the importance of a multidisciplinary approach that includes endocrinologists, neurosurgeons, and radiologists to optimize patient outcomes.

D. Limitations and Future Work

This case report provides valuable insights into the management of hyperprolactinemia, particularly in treatment-resistant prolactinomas, but it is limited by its focus on a single patient. The study's lack of controlled analysis of dietary interventions and alternative therapies prevents a clear understanding of their impact on prolactin levels. Additionally, the absence of genetic or molecular analysis and long-term post-surgical follow-up restricts the ability to fully comprehend the underlying mechanisms of treatment resistance and the durability of surgical outcomes.

Future research should involve larger cohort studies to generalize findings and investigate the role of dietary and lifestyle interventions in managing hyperprolactinemia. Molecular studies exploring genetic markers of treatment resistance could enable more personalized therapeutic strategies. Long-term follow-up post-surgery and randomized controlled trials comparing various treatment modalities would provide deeper insights into effective management and offer better guidance for clinical decision-making in hyperprolactinemia cases.

In conclusion, the case report contributes to the growing body of literature on the management of treatment-resistant hyperprolactinemia. It illustrates the limitations of pharmacological interventions in some cases of prolactinoma and highlights the significant role of surgical intervention in achieving long-term remission. Future research should focus on identifying predictive factors for treatment resistance and exploring the potential of integrative therapies, such as dietary modifications, in managing prolactinomas. This case also reinforces the importance of patient-centered care, with adaptable treatment plans tailored to the individual’s response to therapy.

Ethical Approval and Consent to Participate

The study was conducted in accordance with the ethical standards of the institution and the Declaration of Helsinki. Ethical approval was granted by Tehran University of Medical Sciences (IR.TUMS.MEDICINE.REC.1400.1102). Informed consent was obtained from the patient involved in this case report.

Consent to Publication

Consent for publication was also secured from the patient. All personal identifiers have been removed to maintain the patient’s anonymity.

Data Availability Statement

Data supporting the findings of this study are available within the article. Additional data may be requested from the corresponding author, provided that patient confidentiality is ensured.

Conflict of Interest

The authors declare no conflicts of interest related to this case report.

Funding

No external funding was provided for this study, and all related expenses were covered independently.

Acknowledgment

The authors would like to thank Dr. Seyed Mousa Sadr Hosseini for their participation in the surgery. We also appreciate the patient’s cooperation and trust in sharing their case for this report.

Author Contribution

Hasan Reza Mohamadi: Performed the surgery and monitored drug dosages during the study.

Ava Yektaeian Vaziri: Wrote the manuscript, conducted all aspects of the research, and interacted with the subject.

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No competing interests reported.

A Comparative Case Study of Pituitary Macroadenoma Treatment: No Intervention, Medication, Nutrition, and Endoscopic Transsphenoidal Surgery

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Abstract

Figures

I. INTRODUCTION

II. METHOD

III. RESULTS

IV. DISCUSSION

V. CONCLUSION

Declarations

References

Additional Declarations

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Version 1