Understanding the biology: why GnRH works in PMDD
PMDD is not caused by “too much” or “too little” hormone.
Instead, it is best understood as: A sensitivity of the brain to normal hormonal changes across the menstrual cycle
After ovulation, levels of oestrogen and progesterone rise and fall. In PMDD, these changes can trigger:
Mood swings
Anxiety
Irritability
Low mood
GnRH analogues work by switching off the ovarian cycle entirely.
This removes:
Ovulation
Hormonal fluctuations
The cyclical trigger for symptoms
Up to 70% of women with treatment-resistant PMDD respond to this approach .
GnRH agonists: the traditional approach
Examples include:
leuprolide
goserelin
nafarelin
How they work
GnRH agonists initially stimulate the hormonal system, causing a short “flare” in oestrogen levels. After this, the system becomes desensitised and shuts down.
The result:
Stable, very low hormone levels
No ovulation
No cyclical fluctuation
What the evidence shows
Most of the research in PMDD has been done using injectable GnRH agonists. These studies consistently show:
Significant improvement in both mood and physical symptoms
High response rates in severe, treatment-resistant cases
The downside
Without further treatment, GnRH agonists create a temporary menopause, leading to:
Hot flushes
Sleep disturbance
Brain fog
Bone loss over time
This is why add-back HRT is essential.
Add-back HRT: restoring stability, not fluctuation
One of the biggest shifts in our understanding of PMDD is this: It is not low hormones that help, it is stable hormones
With carefully prescribed continuous (not cyclical) HRT, we can:
Reduce menopausal side effects
Protect bone, heart and brain health
Maintain symptom control
Some women may experience a brief return of symptoms when hormones are reintroduced, but this usually settles once levels stabilise .
GnRH antagonists: the newer option
Examples include:
elagolix
relugolix
These are a newer class of medication and represent an exciting development.
GnRH agonists and antagonists both work to suppress ovulation, but they do so in slightly different ways. Agonists, such as leuprolide or goserelin, initially cause a temporary rise in hormone levels, known as a “flare,” before switching off the hormonal system and leading to stable suppression. They are typically given as injections and, once administered, their effect is relatively fixed. In contrast, GnRH antagonists such as elagolix and relugolix act more directly, blocking the hormone signal straight away without causing an initial flare. They are taken orally, which makes them more flexible and accessible, and their effects can be adjusted more easily by changing the dose. However, while agonists have a stronger evidence base in PMDD and tend to produce very consistent suppression, antagonists are newer in this context and may result in more variable levels of suppression depending on dosing and adherence.
What does the evidence say about antagonists in PMDD?
At present, the evidence is limited.
While these medications are well studied in:
Endometriosis
Fibroids
There is very little direct research in PMDD .
However, from a physiological perspective, they make sense:
They suppress ovulation
They reduce hormonal fluctuation
They can be used in a more tailored way
This makes them a promising future option, particularly for women who cannot access or tolerate injections.
Choosing between agonists and antagonists
In clinical practice, the most important factor is not the drug itself, but: How effectively it creates a stable hormonal environment.
GnRH agonists may be preferred when:
Symptoms are severe
Diagnostic clarity is needed
A reliable, complete suppression is required
GnRH antagonists may be considered when:
Injections are not practical
A more flexible or remote treatment approach is needed
Side effects of agonists are problematic
Are there different types of PMDD?
Emerging research suggests that PMDD is not a single condition.
Some women appear to be:
Sensitive to hormonal fluctuation
Others may be sensitive to progesterone itself
This matters because:
Some women improve on GnRH + HRT
Others may relapse when progesterone is reintroduced
This is an area of active research and personalised care.
The future of treatment
Despite the effectiveness of GnRH therapies, access remains limited.
Barriers include:
Lack of clinician familiarity
Concerns about safety
Practical challenges with injections
There is a growing need for:
Better access to these treatments
Research into oral options
Personalised protocols based on symptom patterns
A more compassionate approach
Historically, some protocols required women to experience a period of induced menopause before starting HRT, to “prove” the diagnosis.
But we now understand that: The goal is not to remove hormones completely, but to remove the instability that triggers symptoms.
This allows for a more compassionate and patient-centred approach:
Minimising unnecessary suffering
Prioritising stability
Tailoring treatment to the individual
Final thoughts
GnRH analogues are one of the most effective tools we have for severe PMDD.
Agonists are well established and highly effective
Antagonists are promising but under-researched
Add-back HRT is essential for safety and long-term use
Most importantly, treatment is evolving.
We are moving away from a one-size-fits-all model towards:
Understanding individual sensitivity
Creating hormonal stability
And delivering care in a way that works for real lives
FAQ
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No, they control symptoms by switching off ovulation. Symptoms usually return if treatment is stopped.
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With appropriate add-back HRT and monitoring, long-term use appears safe, although more research is needed
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No. The effects are reversible once treatment stops.
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We don’t yet have strong evidence in PMDD, but they are a promising alternative.