Gonadotropin-Releasing Hormone Analogues (GnRHa) are drugs that act on the pituitary gland in the brain to cause a temporary menopause.

Preventing the brain-ovary communication that leads to ovulation and hormone production leads to a low, stable hormonal environment that resembles menopause. This is also sometimes called a “chemical menopause.”

By “flattening out” the fluctuations that happen during a menstrual cycle, it allows providers to ‘test’ that the patient has PMDD and not another disorder.

No hormonal fluctuations = No PMDD symptoms.

Examples of these drugs are Lupron, Decapeptyl, Orilissa and Zoladex.

They are often prescribed HRT to provide a steady, continuous dose of hormones. GnRHa also helps confirm an accurate diagnosis of PMDD, as symptoms will resolve (i.e., not happen) when the cycle is entirely suppressed. However, suppose you have another condition that is exacerbated premenstrually (known as PME). In that case, GnRHa may not provide relief from that condition, as the biological source of the issue is different from PMDD.

The chemical menopause also acts as an opportunity to test that the patient can ‘tolerate’ HRT. This is particularly important for those who have an emotional hormone sensitivity, such as PMDD; studies suggest that any change in hormone levels can provoke symptoms among those patients, but those symptoms go away again after one month of the new therapy. Therefore, patience and support are needed to evaluate any treatment change's “true” effects. The symptoms in the first month following the start of HRT (or any changes in HRT) usually subside. So while it can be a difficult start, many with PMDD can take HRT during chemical/surgical menopause.

This process is essential as it will help to dictate if it is safe to go ahead with the surgery, and also can help decide if you need a hysterectomy in addition to ovary removal.

Suppose the GnRHa plus hormone addback (often called a “menopause trial”) improves PMDD symptoms, but the patient is unable or unwilling to continue with GnRHa treatments. In that case, patients may be offered a total hysterectomy with bilateral oophorectomy (removal of the uterus and both ovaries) to once and for all remove the hormonal flux that causes symptoms. Bilateral oophorectomy (removal of the ovaries) eliminates hormone cycling and usually eliminates cyclical symptoms in those with PMDD.

Those accurately diagnosed with PMDD should see significant improvement with cycle suppression.

GnRH analogues offer a significantly superior therapeutic effect in trials compared with vitamin B6, progesterone, and progestogens. This effect appears comparable to that seen for SSRIs (selective serotonin reuptake inhibitors). Data demonstrated a clinically significant beneficial effect over placebo.

While some evidence suggests that ‘add‐back’ therapy can reduce side effects without a demonstrable effect on efficacy, further trials are needed.

GnRHs are currently available as oral spray, nasal spray, injection, and implant (also delivered via injection). The most-used example is an injection called leuprolide or Lupron. This injection shuts down hormone production by the ovaries, causing a reversible menopause in which your hormone levels stay very low and flat. Different versions may be available depending on your country and health care system. Please speak to your provider about what they can offer you.

All the GnRH analogues are very similar chemically, but they come in different forms:

Oral

There is a new oral version of GnRHa called Orilissa - It was approved by the FDA to manage moderate to severe endometriosis pain. It comes in two doses - 150mg and 200mg. This is not FDA-approved for use in treating PMDD. However, some providers may prescribe it off-label for the treatment of PMDD since it is also a GnRH analogue that can be used to produce chemical menopause. There are currently no studies on the efficiency of its use for the treatment of PMDD.

Subcutaneously* either as an injection or as an implant.

These injections are administered in either the buttock or the abdomen. They are not licensed for self-administration, so you will need to have them administered by a nurse. Depending on the type/brand of medication you are offered, they will come in varying strengths and in monthly or three-monthly versions. An example of this type of treatment is Lupron (leuprolide).

*This means it goes under the skin.

Nasal Spray

Nasal sprays such as Synarel (Naferelin) are used once or twice a day (always follow your provider’s instructions).

“I am glad someone warned me about the weird taste of Synarel - it’s a bit strange and like an odd salt water or swimming pool water! You do quickly get used to it, though, and I quickly got in the habit of doing my ‘spray’ just before bed!” —Patient

This experience will differ from patient to patient. Some people will feel better right away - their ovaries will shut down quickly, they have minimal symptoms from this “shut down,” and they start HRT with minimal issues. For others, it will take 2/3 months for the GnRHa agonists to suppress the menstrual cycle. By shutting down the ovaries, you are put into a menopausal state, and many symptoms of menopause can feel a lot like PMDD!

Some may experience undesirable side effects. Most commonly these may include hot flushes, reduced sex drive, headaches, mood changes including depression, vaginal dryness and change in breast size. These symptoms mean the medication is working and is not a reason for discontinuation. HRT is used to counteract the low level of hormones, and if you are feeling these symptoms, then your dose of addback estradiol will need adjusting.

In these first weeks, it is common to have a “flare” in hormone levels. Therefore, you may experience PMDD-like symptoms as your brain adjusts and downregulates its hormonal stimulation to your ovaries.

Chemical menopause can be a difficult process for those with such sensitivities, so it is wise to plan and ensure you have extra support in place. This step in treatment is essential, and despite initial difficulties, it is worth enduring if you can tolerate the side effects.

The IAPMD - PMDD, Oophorectomy, Hysterectomy, & Life After Group is a great place for support, understanding, and hearing other experiences of people going through (or who have been through) the same process.

“I wish someone had warned me that being slammed into menopause is HARD! For those sensitive to hormone fluctuations, the sudden downward drop of hormones can be extremely tough. It felt like constant PMDD for a while, and no one told me it could be this way. I didn’t feel any changes immediately, but months 2/3 were rough. With HRT added in, I began to feel better once everything settled and was stable.” —Patient

The maximum length of using GnRHa treatment used to be 6 months - however this has now changed with the discovery that long-term addback HRT is well-tolerated after a one-month adjustment period. Nowadays, as long as you are using HRT and doing well on the stable level of “add-back” hormones and you are being monitored for risks, then you can stay on this treatment indefinitely. Chemical menopause (especially at a young age) has risks that can be reduced or eliminated with stable add-back of estradiol and progesterone, sometimes referred to as hormone replacement therapy.

Longer-term use of the GnRHa is also used with gynecological disorders; many gynecologists will maintain patients on GnRHa treatments but keep them closely monitored and on Estrogen and Progesterone HRT.

More research is needed on GnRHa treatment and PMDD, but there are plenty of gynecologists who will offer this treatment on a long-term basis rather than refer for surgery.

As with all treatments, there are potential risks and negative side effects.

It is important to note that chemical menopause IS a temporary menopausal state. Although your mood symptoms will hopefully improve once a sufficient estrogen dose has been stable for about one month, you likely will experience some of the unpleasant physical symptoms of menopause (a state of low estrogen) which may include: night sweats, hot flashes, joint aches, fatigue, headaches, dry/itchy skin, low libido, vaginal dryness, insomnia, nausea, heart palpitations, urinary frequency. Also, you are likely to have emotional/cognitive symptoms such as anxiety, low mood, brain fog, and forgetfulness.

It is also possible in some cases that your mood symptoms may worsen initially until adequate estrogen therapy is used.

If you have questions or concerns, please speak to your provider.

Some providers will offer this; however, it is not recommended in any treatment guidelines. There are three essential elements to consider:

1. Ensuring Accurate Diagnosis

This step in treatment can help make an accurate diagnosis. Suppose your ovulation is stopped and your cycle is entirely suppressed. In that case, you should not experience any PMDD symptoms (though you may have menopausal symptoms if you are not on adequate estrogen HRT).

This must be explored to consider other potential diagnoses if you continue to have symptoms.

The surgery is life-changing and invasive - by skipping this step of treatment, there is a risk that you have the surgery and then find out you had PME (premenstrual exacerbation) of another condition, which could have been managed via other treatment.

2. Chemical Menopause can be a Long-Term Option

If you trial GnRHa and tolerate it and add back HRT, well then you can stay on this as a long-term (and reversible) option rather than have invasive surgery and enter surgical menopause.

3. Ensuring you tolerate HRT

This is an opportunity to check that you can live well with stable hormone levels via HRT. We totally understand the concerns that people have when starting HRT, especially if you have a history of reacting negatively to hormone-based treatments. However, HRT can help reduce or eliminate many of the physical risks that come with surgical menopause, and so it is strongly recommended that HRT is used where possible. If you choose not to use HRT, it needs to be an informed decision.

Taking all these points into consideration, it is wise to trial GnRHa treatment before jumping straight to surgery. It is part of the treatment guidelines for a very good reason. No one wants to have unnecessary surgery, especially one that leaves you in surgical menopause, so we would always recommend following official guidance.

Yes, any treatment can lose efficacy over time. There is currently no research about the ongoing effectiveness of GnRHa treatment in those with PMDD/PME. Although is it not fully understood why this may be the case, with some people clinically it is noted by members of the IAPMD Clinical Advisory Board that they do see patients who do well to begin with an GnRHa initially but find that over time it does not continue to suppress the ovarian function as well as at first. 

These medications must suppress ovulation to be effective. If you believe you are still ovulating, you can use at-home urine LH surge tests to determine whether you are ovulating. If you find that you are still ovulating, be sure to share this with your physician, as it means that you have not had a “fair trial” of treatment since it was not effective in producing a menopausal state.