PMS or premenstrual syndrome and endometriosis

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

Premenopausal syndromes and hormones

The traditional view

Premenstrual syndrome is a frequent, well known (4500 hits on pubmed) but poorly understood syndrome, occurring to some extend in most if not all women in the premenstrual period . The symptoms of PMS are variable.

• Some women have mainly brain symptoms or premenstrual dysphoric disorder with feelings as irritability, depression, mood swings, nervousness, irritation, sleep disturbances, character changes and more severe psychiatric syndromes.
• Other women mainly complain  of  ‘progesterone’ effects  as abdominal bloating, water retention and breast tenderness.

Traditional gynecology and endocrinology consider progesterone concentrations or hormone changes  as the driving motor of PMS. It seems logical since PMS occurs in the luteal phase of an ovulatory menstrual cycle. The ‘classic’ but empirical treatment with progesterone orally or intra-vaginally,  unfortunately is not very effective. Even the suppression of ovulation is not that effective according to a recent Cochrane review (5).

What is missing in the literature ?

Traditional gynecology and endocrinology do not consider clinical observation as valuable information. When Evidence Based Medicine becomes a religion what is not proven -preferentially in a RCT-  does not exist.  We recently discussed this in detail for surgery(6). After 30 and 40 years of gynecologic endocrinology and endometriosis we consider important for PMS

• The effect of age : in young women severe PMS is rare; it increases with age and decreases after 45 years
• The importance of an 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 mean effect. Individual women however are different. Well know is the bioavailability of orally administered progesterone (and estrogens) which 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 women to women. 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 obvious 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 no 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. Locally progesterone can act as an immunosuppressant.
• 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.