Introduction 

The hypothalamus and pituitary gland are essential structures located in the brain and play a big role in regulating the endocrine system.¹ Together, they form a system along with the ovaries called the hypothalamic-pituitary-ovarian (HPO) axis, which tightly controls hormone production and female reproduction. Dysfunction in any of the components involved typically results in various disorders that can affect an individual’s fertility, menstrual cycle, lactation and other functions.³ 

One of many HPO disorders is the rare Chiari-Frommel syndrome (CFS), a type of hyperprolactinemic amenorrhea, which occurs after pregnancy (postpartum) in most cases.  This is mainly characterised by irregular menstruation (amenorrhea) and persistent lactation for long periods of time despite no breastfeeding or pregnancy (galactorrhea) and lack of ovulation (anovulation).^1,2,5 These manifestations are the result of abnormally high levels of the prolactin hormone within the blood (hyperprolactinaemia) that tend to happen during pregnancy, typically exceeding 500 mIU/L in AFAB (assigned female at birth).^2,8

Importance of the hypothalamic-pituitary axis

There are various types of hypothalamic-pituitary axis, which involve interaction with different glands of the endocrine system, including the thyroid gland (HPT), adrenal gland (HPA), and ovaries (HPO).³ The HPO axis in particular is heavily involved in CFS. 

The hypothalamus (specifically the tuberal region) is crucial for stimulating the pituitary gland via the release of gonadotropin-releasing hormones (GnRH), which is considered a master regulator of reproduction – influencing the menstrual cycle, puberty and the release of gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Therefore, a deficiency in GnRH is a significant contributing factor in CFS.⁴ The hypothalamus also secretes vasoactive intestinal peptides (VIP) and thyroid-releasing hormone (TRH) that further control prolactin levels.⁶

The pituitary gland, once stimulated by the hypothalamus, releases hormones vital for the regulation of endocrine glands and steroid hormones. This includes LH and FSH, which are essential for reproduction, and prolactin, the hormone responsible for CFS when produced in excess.⁸ Prolactin is the key hormone involved in inducing and maintaining lactation in women. It also suppresses GnRH, thus inhibiting reproductive function.^4,7 

Development of Chiari-Frommel syndrome

Although the precise cause of CFS remains unknown, it is strongly suspected that the dysfunction of the HPO axis leads to abnormal hormone cycles and imbalances, particularly with prolactin, that contribute to the disorder. HPO dysfunction can be due to several factors. Examples include prolactinomas, a disconnect between the hypothalamus and pituitary gland, and intake of antipsychotic medications.^3,8

High levels of prolactin suppress GnRH, which results in a decline in oestrogen levels - this usually happens after giving birth. However, in CFS, prolactin levels unfortunately fail to return to normal. Prolactin usually follows a negative feedback mechanism (switches itself off) on its own production by increasing dopamine release to suppress its own further secretion.⁹ While this is not a direct cause of the syndrome, it leads to main symptoms like galactorrhea and amenorrhea.^6,7 

Excess prolactin and other hormones associated with pregnancy are also thought to give rise to small, microscopic tumours in the pituitary gland (microadenomas) and are suggested as a potential cause.¹ Unfortunately, as CFS is a rare disorder, there is currently limited research on its development and causes.

Clinical symptoms and diagnosis

Symptoms as a result of HPO dysfunction and hormonal imbalance include:^1,2

• Amenorrhea
• Galactorrhea
• Anovulation
• Infertility
• Reduced size of uterus (uterine atrophy) – leading to vaginal dryness
• Emotional distress – depression and anxiety
• Weight gain or obesity
• More general symptoms – headaches, abdominal pain and fatigue

Hormonal evaluation is a form of diagnosis for CFS in which serum prolactin levels in the blood are measured and hyperprolactinemia is detected.² Thyroid-stimulating hormones are also measured, as it is associated with higher prolactin levels.⁶ Imaging tools like MRI or a CT scan can also be used to detect and monitor the presence of tumours in the pituitary gland.^1,2

It is important that the diagnosis is accurate, as some symptoms of CFS may resemble other similar conditions, such as the Forbes-Albright syndrome and Ahumada-del Castillo syndrome. For instance, they all involve hyperprolactinemia, galactorrhea and amenorrhea, respectively, despite being completely unrelated to pregnancy and childbirth.^1,2

Treatment

In 40% of CFS cases, the disorder spontaneously goes away on its own within five years without requiring hormonal treatment.^1,2,5

However, for patients who do not experience spontaneous remission, they must undergo a range of treatments to manage CFS symptoms:

Bromocriptine is a dopamine receptor agonist that aims to lower prolactin levels by inhibiting its release from the pituitary, therefore restoring reproductive function, including regular menstruation and ovulation.¹⁰  Bromocriptine is commonly used for endocrine disorders like CFS, proving its efficacy as a treatment. 

Cabergoline is also a dopamine agonist with fewer side effects despite greater potency compared to bromocriptine. However, healthcare professionals and patients must be cautious of administering high dosages, as they have been linked to the thickening of the heart valves (valvular heart disease).⁷

Hormone therapy is another treatment for CFS that has been trialled and evaluated many times, in which some patients have shown improvement in their symptoms. More recently, the administration of oestrogen-progesterone and chorionic gonadotropin hormone therapies has demonstrated symptom improvement in patients. Whereas older therapies like oestrogen, androgens and thyroid hormone therapies on their own failed to show consistent effects.² Use of contraceptive pills can be a potential alternative.⁷

Surgical intervention can also be helpful in more prolonged, severe cases where patients may have a pituitary tumour causing HPO axis dysfunction and hormonal imbalances.^1,2

Summary

Chiari-Frommel syndrome is typically a postpartum endocrine disorder that displays an absence of menstruation, persistent lactation and stimulation of the nipples, lack of ovulation and sometimes infertility. While there is a lack of clarity on the direct causes of this syndrome, it’s highly suspected that the disorder is related to an impairment of the hypothalamic-pituitary axis or dysfunction of its components. This can be due to a disconnection within the axis or a tumour obstructing the pituitary, inhibiting its function.

The HPO axis is vital for reproductive function and hormone regulation. The primary hormone involved in CFS is prolactin, which is significantly increased in the blood. This causes a cascade of other problems – a decrease in GnRH and estrogen production, which is the basis of the main CFS symptoms (galactorrhea, amenorrhea, anovulation). 

Blood tests for prolactin and other related hormones are relied on for diagnosis. As for treatment, dopamine agonists like bromocriptine and cabergoline are the most significant and currently the first-line therapies due to their efficacy. Hormone therapy, as well as surgical intervention, are alternatives in more severe cases. Fortunately, the disorder can resolve on its own, restoring normal reproductive function.