How Estrogen Fluctuations Before Diagnosis Affect the Size Prolactin-secreting Tumors (OEMacroPrL)

January 21, 2026 updated by: Hospices Civils de Lyon

Influence of Pre-diagnostic Estrogen Fluctuations on the Development of Prolactin-Secreting Macroadenomas or Microadenomas: A Comparative Study Conducted at Hôpital Louis Pradel

Prolactinomas are the most common pituitary adenomas, representing about two-thirds of clinically relevant cases. Their prevalence is around 50 per 100,000 individuals, with an incidence of 3-5 new cases per 100,000 per year and has been rising in recent decades.

They may increase morbidity and mortality due to several factors:

  • Hormone hypersecretion: excess prolactin causes galactorrhea, amenorrhea, and infertility.
  • Mass effect: macroadenomas can compress adjacent structures, leading to headaches, visual loss, or neurological symptoms.
  • Treatment complications: medical or surgical treatments may carry risks.

A marked sex difference exists, with a male-to-female ratio of 1:5-1:10, and peak diagnosis in women aged 25-44. This disparity disappears after menopause, supporting a potential role of estrogens in tumor development. Lactotrope cells, from which prolactinomas arise, are estrogen-sensitive, unlike other pituitary tumor cells (e.g., somatotrophs, gonadotrophs).

A large 2022 prospective cohort (nurses) suggested a possible association between pituitary adenomas and both combined oral contraceptives (COCs) and hormone therapy (HT). However, limitations included self-reported diagnoses, lack of adenoma characterization, and contradictory findings (association with HT but not consistently with COCs). A 2009 case-control study including all adenomas found no link with hormonal contraception, while older studies from the 1980s assessed high-dose contraceptives no longer in use.

Microprolactinomas are 4-5 times more frequent than macroprolactinomas (≥10 mm). Distinguishing between the two is essential, as they differ in clinical presentation, prognosis, and sex distribution. Macroadenomas are more common in men, possibly due to delayed diagnosis, as symptoms such as decreased libido are less specific, whereas women often present with amenorrhea or galactorrhea. However, studies suggest tumor size is not directly linked to symptom duration, indicating other factors may explain macroadenoma development.

Why some patients develop macro- rather than microadenomas remains unclear. Estrogen exposure is a possible explanation. It is therefore relevant to investigate whether women with macroprolactinomas had greater exposure to endogenous estrogens (early menarche, late menopause, pregnancies, breastfeeding) or exogenous estrogens (contraception, menopausal HT) compared to women with microprolactinomas.

The hypothesis is that women with macroprolactinomas were exposed to higher cumulative levels of estrogens before diagnosis than women with microprolactinomas.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Observational

Enrollment (Estimated)

180

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Patients included in this study will be identified from the COLLEMARA database, used within the Hospices Civils de Lyon. This database, specifically dedicated to rare diseases, provides a structured registry of patients followed for rare pituitary disorders, such as prolactinomas.

For the purpose of this study, the COLLEMARA database will be used solely to identify eligible patients, based on the coded diagnosis of "prolactinoma." The study population will consist of female patients whose diagnosis was made between 2013 and 2023 and who meet the other inclusion criteria.

A total of 180 patients will be included: 60 in the case group ("macroprolactinomas") and 120 in the control group ("microprolactinomas").

Description

Inclusion Criteria of cases :

  • Female patients aged ≥ 18 years at recruitment (diagnosis may have occurred before age 18).
  • Diagnosis of a prolactin-secreting macroadenoma established between January 2013 and December 2023. The diagnosis may have been made either in the Endocrinology Department of Hôpital Louis Pradel or by another medical team, whether within or outside the hospital setting. However, follow-up or part of the follow-up must have been performed in the Endocrinology Department of Hospices Civils de Lyon (HCL)
  • Diagnosis established by : A hypothalamic-pituitary MRI centered on the sella turcica, performed with gadolinium injection, including fine T1-weighted coronal and sagittal slices (1.5-3 mm), showing an adenoma with at least one axis measuring > 10 mm, AND Serum prolactin > 100 µg/L, or 24-100 µg/L with either a favorable response to medical therapy or histopathological confirmation after surgery.
  • Ability to understand the study and provide informed non-opposition.

Inclusion Criteria of controls :

  • Female patients aged ≥ 18 years at the time of recruitment (diagnosis may have occurred before age 18).
  • Diagnosis of a prolactin-secreting microadenoma established between January 2013 and December 2023. The diagnosis may have been made in any medical center, but follow-up or part of the follow-up must have been carried out in the Endocrinology Department of Hôpital Louis Pradel.
  • Diagnosis must be based on: A hypothalamic-pituitary MRI centered on the sella turcica, performed with gadolinium injection, including fine T1-weighted coronal and sagittal slices (1.5-3 mm), showing a prolactin-secreting adenoma with all axes measuring < 10 mm, AND A biological assessment performed outside any condition likely to bias results (significant stress, physical exertion, pregnancy, or intake of hyperprolactinemia-inducing drugs unrelated to prolactinoma treatment), showing serum prolactin > 24 µg/L.
  • Ability to understand the nature and implications of the study and to provide informed non-opposition to participation.

Exclusion Criteria of cases :

  • Presence of a non-secreting macroadenoma.
  • History of isolated hyperprolactinemia or an isolated pituitary lesion documented prior to 2013, without subsequent direct diagnosis of prolactinoma.
  • Presence of a known genetic abnormality or a genetic syndrome predisposing to the development of a prolactin-secreting adenoma.

Exclusion Criteria of controls :

  • Presence of a non-secreting microadenoma.
  • Uncertain diagnosis of adenoma with an ongoing therapeutic trial.
  • Isolated hyperprolactinemia without evidence of adenoma.
  • Hyperprolactinemia or pituitary lesion without hyperprolactinemia documented prior to 2013, without subsequent direct diagnosis of prolactinoma.
  • Presence of a known genetic abnormality or a genetic syndrome predisposing to the development of a prolactin-secreting adenoma

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Women with a macroprolactinoma
Women with prolactin-producing macroadenomas diagnosed between 2013 and 2023 Followed by the Hospices Civiles de Lyon, Hôpital Cardiologique of Bron.
Other: Standardized questionnaire

The intervention is a questionnaire which will be administered only if informations available on medical files are not sufficient.

1 mounth before questionning our cases and controls, they will receive a participant information note.

It will be administered primarily by telephone. If the patient prefers not to answer by telephone, a paper version will be mailed to her. In this case, she will have up to two months to return the completed questionnaire by post.

The questionnaire will collect detailed information on potential exposures to estrogens and reproductive history.
Women with a microprolactinoma
Women with prolactin-producing microadenomas diagnosed between 2013 and 2023 Followed by the Hospices Civiles de Lyon, Hôpital Cardiologique of Bron.
Other: Standardized questionnaire

The intervention is a questionnaire which will be administered only if informations available on medical files are not sufficient.

1 mounth before questionning our cases and controls, they will receive a participant information note.

It will be administered primarily by telephone. If the patient prefers not to answer by telephone, a paper version will be mailed to her. In this case, she will have up to two months to return the completed questionnaire by post.

The questionnaire will collect detailed information on potential exposures to estrogens and reproductive history.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
number of patients exposed to combined estrogen-progestin contraception
Time Frame: week 4
Identify the estrogen-dependent risk factor
week 4
number of patients exposed to menopausal hormone therapy
Time Frame: week 4
Identify the estrogen-dependent risk factor
week 4
number of patients exposed to progestin-only treatment
Time Frame: week 4
Identify the estrogen-dependent risk factor
week 4
number of patients exposed to Ovarian Stimulation
Time Frame: week 4
Identify the estrogen-dependent risk factor
week 4
Age at First Use of Hormonal Contraception
Time Frame: week 4
Identify the estrogen-dependent risk factor
week 4
Age at Menarche
Time Frame: week 4
Identify the estrogen-dependent risk factor
week 4
Age at Menopause
Time Frame: week 4
Identify the estrogen-dependent risk factor
week 4
Age at First Live Birth
Time Frame: week 4
Identify the estrogen-dependent risk factor
week 4
Nulliparity
Time Frame: week 4
Identify the estrogen-dependent risk factor
week 4
Number of Pregnancies Carried to Viability
Time Frame: week 4
Identify the estrogen-dependent risk factor
week 4
Exposure to Breastfeeding defined as the total cumulative duration of breastfeeding across all pregnancies, expressed in months. • None: 0-1 month • Moderate: 1-12 months • High: >12 months
Time Frame: week 4
Identify the estrogen-dependent risk factor
week 4

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hospices Civils de Lyon

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 6, 2026

Primary Completion (Estimated)

January 6, 2027

Study Completion (Estimated)

January 6, 2027

Study Registration Dates

First Submitted

November 19, 2025

First Submitted That Met QC Criteria

December 3, 2025

First Posted (Actual)

December 5, 2025

Study Record Updates

Last Update Posted (Actual)

January 22, 2026

Last Update Submitted That Met QC Criteria

January 21, 2026

Last Verified

January 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 69HCL25_0853

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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