Premenstrual syndrome does not occur if there is no ovarian function. Obviously, it does not occur before puberty or after the menopause, or after oophorectomy; it does not occur during pregnancy. However, it is important to realize that hysterectomy with conservation of the ovaries does not often cure premenstrual syndrome, as patients are left with the usual cyclical symptoms and cyclical headaches. This condition, best-called the ‘ovarian cycle syndrome’, is usually not recognized to be hormonal in etiology, as there is no reference point of menstruation. The failure to make this diagnosis is regrettable because these monthly symptoms of depression, irritability, mood change, bloating, and headaches, which might affect the woman for most days in the month with only perhaps one good week each month, can easily be treated with transdermal estrogens which suppress ovarian function and thus remove the symptoms.
A medical Battey’s operation can be achieved by the use of gonadotropin-releasing hormone (GnRH) analogs and Leather and co-workers have demonstrated that 3 months of Zoladex ® therapy cures all the symptom groups of premenstrual syndrome. The women do, of course, have hot flushes and sweats but these are usually far preferable to the cyclical depression, irritability and headaches. The long-term risk of Zoladex ® therapy is bone demineralization, but the same group showed that add-back with a product containing 2 mg estradiol valerate and cyclical levonorgestrel (Nuvelle ®) maintains the bone density at both the spine and the hip. Most of the premenstrual syndrome symptoms remain improved with this add-back but bloating, tension and irritability recur — probably due to the cyclical progestogen. Livial ® may be a better add-back preparation.
In a Scandinavian study, Sundstrom and colleagues used low-dose GnRH analogs (100 µg b userelin) with good results on the symptoms of premenstrual syndrome, but the treatment still caused anovulation in as many as 56% of patients. Danazol is another method for treating premenstrual syndrome, by inhibiting pituitary gonadotropins, but it has side-effects including androgenic and virilizing effects. When used in the luteal phase alone it only relieved mastalgia but not the general symptoms of premenstrual syndrome, though side-effects were minimal.
Greenblatt and co-workers showed the effects of an anovulatory dose of estrogen implants for the use of contraception. The first study of its use for premenstrual syndrome was by Magos and co-workers using 100 mg estradiol implants — the dose that had been shown to inhibit ovulation by using ultrasound and day-21 progesterone measurements in earlier studies by the same group. This showed a huge 84% improvement with placebo implants but the improvements of every symptom cluster were greater in the active estradiol group. In addition, the placebo effect usually waned after a few months compared with a continued response to estradiol. These patients, of course, were also given oral progestogen 12 days per month to prevent endometrial hyperplasia and irregular bleeding. It was clear that the addition of progestogen attenuated the beneficial effect of estrogen. Subsequently, a placebo-controlled trial of cyclical levonorgestrel in well-estrogenized hysterectomized women reproduced the typical symptoms of premenstrual syndrome. This study of cyclical oral progestogen in the estrogen-primed woman is the model for premenstrual syndrome. It is also significant that progestogen intolerance is one of the principal reasons why older, postmenopausal women stop taking hormone replacement therapy, particularly if they have a past history of premenstrual syndrome or progesterone intolerance. It is common for progestogens to cause premenstrual syndrome-like symptoms in these women in the same way endogenous cyclical progesterone secretion is the probable fundamental cause of premenstrual syndrome.
Our group still uses estradiol implants — often with the addition of testosterone for loss of energy and loss of libido — in our premenstrual syndrome clinics but we have reduced the estradiol dose, never starting with 100 mg. We now insert pellets of estradiol, 50 or 75 mg, with 100 mg of testosterone. These women must have endometrial protection by oral progestogen or a Mirena ® levonorgestrel-releasing intrauterine system (LNGIUS). As women with premenstrual syndrome respond well to estrogens but are often intolerant to progestogens, it is commonplace for us to reduce the orthodox 13-day course of progestogen to 10 or 7 days starting, for convenience, on the first day of every calendar month. Thus, the menstrual cycle is reset with the woman having the obvious additional advantage of 12 periods/year instead of 13. She can also easily plan her withdrawal bleeds to avoid holidays and other important functions.
The Mirena ® IUS also plays a vital role in preventing premenstrual syndrome-like symptoms as it performs its function of protecting the endometrium without systemic absorption. A recent study has shown a 50% decrease in hysterectomies in our practice since the introduction of the Mirena ® IUS in 1995. With its profound effect on menorrhagia and fewer progestogenic side-effects, Mirena ® looks a very promising component of premenstrual syndrome treatment in the future.
Hormone implants are not licensed in all countries and are unsuitable for women who may wish to easily discontinue treatment in order to become pregnant. Estradiol patches are an alternative and our original double-blind cross-over study used a 200 µg estradiol patch twice weekly. This produced plasma estradiol levels of 800 pmol/1 and suppressed luteal phase progesterone and ovulation. Once again this treatment was better than placebo in every symptom cluster of premenstrual syndrome. Figure 4 shows the response to estradiol treatment and placebo in a 6-month cross-over study. This is now our treatment of choice for severe premenstrual syndrome.
Subsequently, a randomized but uncontrolled observational study from our premenstrual syndrome clinic indicated that premenstrual syndrome sufferers could have the same beneficial response to 100 µg patches as they do with the 200 µg d ose. They also have fewer symptoms of breast discomfort and bloating and there is less anxiety from the patient or general practitioner about high-dose estrogen therapy . Twenty-one-day progesterone assays in the patients receiving 100 µg showed low anovulatory levels prompting the intriguing notion that even this moderate dose might reliably suppress ovulation and be contraceptive. Clearly, a great deal of work must be done before we can suggest that this treatment is effective for birth control, but it is of great importance because many young women using this therapy for premenstrual syndrome would be pleased if it was also an effective contraceptive. This is a study that needs to be conducted.
The original studies outlined in this paper are all scientifically valid placebo-controlled trials showing a considerable improvement of premenstrual syndrome symptoms with estrogens. Although this treatment is used by most gynecologists in the United Kingdom, its value has not been exploited by psychiatrists anywhere in the world. We believe that the benefit of this therapy in severe premenstrual syndrome is due to the inhibition of ovulation but there is probably also a central mental tonic effect. Klaiber and co-workers in their study of high-dose Premarin ® showed this, and our other psycho-endocrine studies of climacteric depression and postnatal depression have shown the benefit of high-dose transdermal estrogens for these conditions, which is not related to or dependent on suppression of ovulation.
Ultimately there are some women who, after treatment with estrogens and Mirena ® coils will prefer to have a hysterectomy in order to remove all cycles with a virtual guarantee of improvement of symptoms. This should not be seen as a failure or even the treatment of last resort as it does carry many other advantages.
It is important that those women who have had a hysterectomy and bilateral salpingooophorectomy have effective replacement therapy, ideally with replacement of the ovarian androgens. Implants of estradiol 50 mg and testosterone 100 mg are an ideal route and combination of hormones for this long-term therapy post-hysterectomy, with a continuation rate of 90% at 10 years. We have a study of 47 such patients who have had a hysterectomy, bilateral salpingo-oophorectomy and implants of estradiol and testosterone for severe premenstrual syndrome, who have gone through many years of treatment with transdermal estrogens and cycle progestogens or Mirena ® coil. The symptoms are removed in all patients and all but one was ‘very satisfied’ with the outcome.