PMS or premenstrual syndrome and endometriosis

A recent question by a patient prompted this short review premenstrual syndrome(1-4).

The traditional view

PMS symptoms

Premenstrual syndrome is a frequent (4500 hits on Pubmed) but poorly understood syndrome, occurring to some extent in most, if not all, women. The symptoms are variable.

• Some women have mainly brain symptoms or premenstrual dysphoric disorder with feelings such as irritability, depression, anxiety, mood swings, nervousness, irritation, concentration problems, sleep disturbances, food craving and character changes up to more severe psychiatric syndromes.
• Other women complain of  abdominal pain or bloating, water retention, constipation, skin problems and breast tenderness.

Traditionally, gynaecology and endocrinology consider progesterone  and hormone changes as the driving motor of PMS. This seems logical since PMS occurs in the luteal phase after ovulation. The ‘classic’ although empirical treatment uses progesterone, but is, unfortunately, not very effective. Even the suppression of ovulation is not that effective, according to a recent Cochrane review (5).

Treatment of PMS

Whilst there is no ‘magic bullet’ to eradicate Premenstrual Syndrome, relief can be attempted by sugar fixe to a hysterectomy and a lot of things in between, such as lifestyle, not enough sleep, lack of aerobic exercise, too much caffeine or alcohol, stress or tobacco smoke. Why not take up yoga or exercise regularly  – exercise can do wonders to reduce cramps!

What is missing?

endofound award

In the pyramid of evidence of Evidence based Medicine, clinical observation clinical observation is considered a personal opinion with little value. We recently discussed this problem for endometriosis (6, 7) and emphasised the importance of collective experience (8), which is a Bayesian process of learning (9-10), published the 10 cardinal sins of endometriosis management (11) and discussed this when receiving the the Harry Reich Endofound award in New York. 

Our management of PMS

Our management is based on observational facts 

• The effect of age: in young women, severe PMS is rare; it increases with age and decreases after 45 years
• The importance of a uterus: severe PMS is extremely rare in the absence of a uterus, even in women with signs of ovulation and a regular ovulatory cycle.
• The individual variability in progesterone effect. Medicine and research tend to focus on the average effect in the average woman. Individual women, however, are different. Well know is that the bioavailability of orally administered progesterone (and estrogens) varies at least 4 times from woman to woman. Well know also is the individual variability in progesterone effect (ovulation inhibition dose and Clauberg test), which varies even more from woman to woman. Considering that individual variability has a Gaussian distribution, the real individual variability between extreme women will be way over 10 times. Thus in different women, 1 and 10 mg can have the same effect. This is clearly demonstrated in hormone replacement therapy.
• Brain effects of progesterone are poorly understood, especially the interplay with estrogens and the effect of 5alfa-reduced progestins. This is difficult to study, but poorly understood should not be interpreted as not having an effect. Examples of brain effects are the hypnotic effects in rodents and the beautiful studies on libido and sexuality in primates. Extreme aggressiveness in women occurs almost exclusively in the premenstrual period. 
• The role of progesterone in the basal endometrium, in the growth of endometriosis and of fibroids is poorly understood. In addition, we recently reported that deep endometriosis is heterogeneous and that in some women, progesterone can stimulate endometriosis instead of inhibiting growth.
• The brain effects of the available progesterone receptor modulators (antagonists and partial agonists) are poorly investigated or understood

Therapy of PMS

PMS has characteristics of an over-sensitivity to progesterone either as a direct brain effect or eventually indirectly through an effect on the uterus.

Therapy requires understanding the potential mechanisms involved, in which inter-individual variability in sensitivity and metabolism plays an important role.

Individualisation of therapy, including taking into consideration progesterone receptor modulators and first pass effect in the uterus, therefore, are the cornerstones of therapy.

Prof P.R. Koninckx    Drssa A. Ussia Gruppo Italo Belga

Reference List

1. Sepede G, Sarchione F, Matarazzo I, Di Giannantonio M, Salerno RM. Premenstrual Dysphoric Disorder Without Comorbid Psychiatric Conditions: A Systematic Review of Therapeutic Options. Clinical neuropharmacology 2016;39:241-61.
2. Ryu A, Kim TH. Premenstrual syndrome: A mini-review. Maturitas 2015;82:436-40.
3. Kwan I, Onwude JL. Premenstrual syndrome. BMJ clinical evidence 2015;2015.
4. Baker LJ, O’Brien PM. Premenstrual syndrome (PMS): a peri-menopausal perspective. Maturitas 2012;72:121-5.
5. Naheed B, Kuiper JH, Uthman OA, O’Mahony F, O’Brien PM. Non-contraceptive oestrogen-containing preparations for controlling symptoms of premenstrual syndrome. Cochrane Database Syst Rev 2017;3:Cd010503.
6. Koninckx PR, Ussia A, Zupi E, Gomel V. Evidence-Based Medicine in Endometriosis Surgery: Double-Blind Randomized Controlled Trial Versus the Consensus Opinion of Experts. J Minim Invasive Gynecol 2017;24:692-4.
7. Koninckx PR, Ussia A, Alsuwaidi S, Amro B, Keckstein J, Adamyan L et al. Reconsidering evidence-based management of endometriosis. Facts Views Vis Obgyn 2022;14:225-33.
8. Wattiez A, Schindler L, Ussia A, Campo R, Keckstein J, Grimbizis G et al. A proof of concept that experience-based management of endometriosis can complement evidence-based guidelines. Facts, Views and Vision in ObGyn 2023;15:197-214.
9. Koninckx PR, Koushik A, Tulandi T. Truth, soft lies, statistics and experience in managing endometriosis. JOGC 2024;in press.
10. Koninckx PR, Wattiez A, Saridogan E. Statistics, truth finding and predictions: what every gynaecologist and researcher should know. Facts Views Vis Obgyn 2023;15:95-7.
11. Koninckx PR, Ussia A, Gordts S, Keckstein J, Saridogan E, Malzoni M et al. The 10 “Cardinal Sins” in the Clinical Diagnosis and Treatment of Endometriosis: A Bayesian Approach. J Clin Med 2023;12:4547