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NCT Number: NCT07268183

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

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.

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Key information

Conditions

Prolactinoma Adenoma Brain Diseases Brain Neoplasms Central Nervous System Diseases Central Nervous System Neoplasms Endocrine Gland Neoplasms Endocrine System Diseases Hypothalamic Diseases Hypothalamic Neoplasms Macroprolactinoma Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Glandular and Epithelial Nervous System Diseases Nervous System Neoplasms Pituitary Diseases Pituitary Neoplasms Supratentorial Neoplasms

Age range

18 year and older

Sex eligibility

Female

Study type

Observational

Primary location

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Standardized questionnaire

Other

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.

Primary outcomes

  1. number of patients exposed to combined estrogen-progestin contraception

    Time frame: week 4

    Identify the estrogen-dependent risk factor

  2. number of patients exposed to menopausal hormone therapy

    Time frame: week 4

    Identify the estrogen-dependent risk factor

  3. number of patients exposed to progestin-only treatment

    Time frame: week 4

    Identify the estrogen-dependent risk factor

  4. number of patients exposed to Ovarian Stimulation

    Time frame: week 4

    Identify the estrogen-dependent risk factor

  5. Age at First Use of Hormonal Contraception

    Time frame: week 4

    Identify the estrogen-dependent risk factor

  6. Age at Menarche

    Time frame: week 4

    Identify the estrogen-dependent risk factor

  7. Age at Menopause

    Time frame: week 4

    Identify the estrogen-dependent risk factor

  8. Age at First Live Birth

    Time frame: week 4

    Identify the estrogen-dependent risk factor

  9. Nulliparity

    Time frame: week 4

    Identify the estrogen-dependent risk factor

  10. Number of Pregnancies Carried to Viability

    Time frame: week 4

    Identify the estrogen-dependent risk factor

  11. 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

Study contacts

Contact information is provided by the study sponsor or research team.

Gerald RAVEROT, Pr

CONTACT

[email protected]

04 27 85 66 66 ext. +33

Mathilde BLARY

CONTACT

[email protected]

Sponsors and collaborators

Lead sponsor

Hospices Civils de Lyon

Other

Registry information

Official study title

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

Acronym: OEMacroPrL

Important dates

Study start
2026
Primary completion
2027
Study completion
2027
First posted
Dec 5, 2025
Registry last updated
Jan 22, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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