Best Practice & Research Clinical Obstetrics and Gynaecology

Vol. 22, No. 2, pp. 251–260, 2008

doi:10.1016/j.bpobgyn.2007.07.001
available online at http://www.sciencedirect.com

Hormonal management of premenstrual

syndrome

Sa’adatu Bose Usman * MBChB

Specialist Registrar in Obstetrics and Gynaecology

Radha Indusekhar MRCOG

Locum Consultant in Obstetrics and Gynaecology

Shaughn O’Brien FRCOG

Professor and Consultant in Obstetrics and Gynaecology
Department of Obstetrics and Gynaecology, University Hospital of North Staffordshire,
Stoke on Trent ST4 6QG, UK

Premenstrual syndrome (PMS) is a psychological and somatic disorder of unknown aetiology.

The symptoms of PMS regularly occur during the luteal phase of the menstrual cycle and resolve
by the end of menstruation. The severe and predominantly psychological form of PMS is called
‘premenstrual dysphoric disorder’. PMS results from ovulation and appears to be caused by the
progesterone produced following ovulation in women who have enhanced progesterone sensi-
tivity. This enhanced sensitivity may be due to neurotransmitter dysfunction. Treatment is aimed
at suppressing ovulation or reducing progesterone sensitivity. This chapter will describe the role
of hormones and hormonal treatments in PMS.

Key words: premenstrual syndrome; hormonal management; oestrogens; progesterone; pro-

gestogens; combined oral contraceptives; drosperinone; gonadotrophin-releasing hormone
analogues.

Premenstrual syndrome (PMS) is a range of physical, psychological and behavioural

symptoms that are not due to any organic disease, that occur during the luteal phase
of the menstrual cycle and disappear at the onset of menstruation.1 The morbidity of
PMS is due to its severity and chronicity in a subset of women and the resulting

* Corresponding author. Tel./Fax: þ44 1782 552472.

E-mail address: sau691@yahoo.co.uk (Sa’adatu B. Usman).
1521-6934/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved.
252 Sa’adatu B. Usman et al

impairment in work, family relationships and daily activities.2 This disorder can mani-
fest with a wide variety of symptoms, including depression, mood lability, abdominal
pain, breast tenderness, headache and fatigue.3 At least one premenstrual symptom
occurs in 95% of women of reproductive age. Women with more affective symptoms
are classified as having premenstrual dysphoric disorder (PMDD).3 The main treat-
ment strategies involve ovulation suppression or targeting central nervous system
components that are thought to be involved in the aetiology of PMS.

AETIOLOGY

The exact aetiology of PMS remains unknown, although several theories have been
proposed implicating several hormones and neurotransmitters. The sex steroids pro-
duced by the corpus luteum of the ovary are thought to be symptom provoking, as
the cyclicity disappears in anovulatory cycles when a corpus luteum is not formed.4
Ablation of the ovarian endocrine cycle by oophorectomy or by the administration
of gonadotrophin-releasing hormone (GnRH) analogues is associated with the parallel
elimination of PMS symptoms.5 In women whose ovarian cycles have ceased (due to
the menopause or bilateral oophorectomy) and who subsequently receive hormone-
replacement therapy (HRT), a significant percentage redevelop PMS symptoms during
the progestogen phase of therapy.6
The neurotransmitters within the brain involved in PMS symptoms are the serotonin
and gamma-aminobutyric acid (GABA) systems. It has been proposed that serotonin
deficiency in women with PMS enhances sensitivity to progesterone.7 The efficacy of
selective serotonin re-uptake inhibitors (SSRIs) in the treatment of PMS/PMDD
supports the influence of serotonin in the aetiology of PMS.
GABA is one of the most important inhibitory neurotransmitters in the human
brain; one-third of brain synapses utilize GABA. Clinical studies have reported low
levels of GABA in the plasma and cerebrospinal fluid of patients with mood disorders.8
In patients with PMS, allopregnanolone levels are low in the follicular and luteal
phases.7,9 This appears to be due to impaired synthesis of allopregnanolone by the cor-
pus luteum and other steroidogenic organs.10 Allopregnanolone has a bimodal action
on negative mood symptoms similar to benzodiazepines, barbiturates and alcohol. In
high doses, it produces anxioloytic, anti-aggressive, sedative and anti-epileptic effects.
In low doses, it causes severe emotional reactions in a subset of individuals (2–3%) and
moderate reactions in up to 20% of women.11,12

SYMPTOMS

Symptoms of PMS can be somatic, psychological, behavioural or a combination of all

three forms. These symptoms are recurrent, occurring during the luteal phase of
the menstrual cycle and resolving by the end of menstruation.13 Women with PMS ex-
perience a wide range of symptoms that can be quite varied in terms of severity. Some
women experience such severe symptoms that it is emotionally and physically
disabling. PMDD is the extreme and mostly psychological form of PMS, and affects
2–6% of women who are menstruating.14
Typical psychological symptoms of PMS include anxiety, irritability, depression, mood
swings, sleep disorders, loss of self control, fatigue, decreased interest and altered in-
terest in sex.15 Somatic symptoms are prevalent and they include breast tenderness,
weight gain, headaches, change in appetite, general aches and pain, and feeling bloated.15
 Hormonal management of premenstrual syndrome 253

Some medical conditions can be exacerbated premenstrually. Some of these condi-

tions are affective disorders, anxiety, asthma, migraine, epilepsy, rheumatoid arthritis,
eating disorders and substance misuse.16,17

DIAGNOSIS

Symptoms of PMS occur during the luteal phase of the menstrual cycle and disappear
by the end of menstruation. The main feature of PMS is the absence of symptoms in
the days from the end of menstruation to ovulation. To diagnose PMS, the timing of
symptoms in relation to periods has to be established. This is achieved clinically using
prospective calendars or menstrual charts. For the diagnosis of PMS, symptoms should
be confirmed prospectively by daily rating in at least two consecutive menstrual
cycles.15
There is currently no biochemical test for the diagnosis of PMS. Physical examina-
tion only helps to exclude other conditions that mimic the physical symptoms of
PMS.17

HORMONAL THERAPY IN PMS

This treatment approach involves manipulation of the hormones that are believed to
be responsible for causing PMS symptoms. Hormone therapy can eliminate the men-
strual cycle and suppress ovulation. Over the years, several hormones have been used
for this purpose.

Progesterone and progestogens

The rationale for the use of progesterone and progestogens in the treatment of PMS
is based on the hypothesis that deficiency of progesterone and its derivatives is the
cause of PMS. However, there is no consistent evidence of low levels of progesterone
in sufferers of PMS. A recent systematic review18 on the effectiveness of progester-
one in the treatment of PMS found that studies differed in route of administration
(oral, rectal or vaginal), dose, duration of treatment and selection of participants.
As a result, outcomes also differed. This made combination of data for a meta-analysis
impossible.
The review considered 17 studies but only two trials were included. One of the
studies19 showed a statistically significant improvement with progesterone compared
with placebo in the per-protocol analysis but not in the intention-to-treat analysis,
except for the first cycle. The other study20 found no statistical difference between
oral progesterone, vaginally absorbed progesterone and placebo. The authors of the
review were unable to conclude whether or not progesterone was an effective treat-
ment for PMS. Change in length of menstrual cycle was the only adverse event in the
progesterone group compared with the placebo group that reached statistical signif-
icance. Drowsiness and dizziness were frequently reported in women on oral proges-
terone, and vaginal irritation was frequently reported in women on vaginal
progesterone.
Dydrogesterone, norethisterone and levonogestrel are progestogens used for
PMS therapy on the basis of their progesterone-like action. Progestogens have
been shown to produce no clinically significant improvement in the management of
PMS.21
254 Sa’adatu B. Usman et al

Oestrogen

Hormonal therapy in PMS is geared towards producing anovulation. There is some

evidence that oestrogenic suppression of ovarian function eliminates PMS.22,23
Oestrogen is used in the form of implants, patches or gel. The first study to show
the anovulatory effects of oestradiol implants for use in PMS was by Magos et al.24
They used 100-mg oestradiol implants. This study showed that oestradiol implants
were superior to placebo implants in the entire symptom clusters of PMS. These
patients were also given oral progestogen in the form of norethisterone 5 mg for 7
days every cycle to prevent endometrial hyperplasia. When progestogens are used
to protect the uterus from the untoward side-effect of unopposed oestrogen, PMS-
like symptoms may be re-introduced. This problem can be managed effectively by
using local progestogens, such as levonorgestrel-releasing intra-uterine systems, as
this avoids systemic absorption.17

Combined oral contraceptive pill

The combined oral contraceptive pill (COCP) prevents ovulation and should be effec-
tive for the treatment of PMS. However, evidence from the limited studies available
does not support the efficacy of oral contraceptive agents containing progestins derived
from 19-nortestosterone.25 The combination of oestrogen and progestin may produce
symptoms similar to PMS, such as water retention and irritability. The introduction of
an oral contraceptive pill containing low-dose ethinyl oestradiol and a new progesto-
gen, drosperinone has offered clinical efficacy for PMS/PMDD.26 Drospirenone is
a spironolactone derivative with antimineralocorticoid and anti-androgenic activity.
Drospirenone’s anti-androgenic activity makes it effective in the reduction of acne
and seborrhoea. The antimineralocorticoid activity helps to reduce some of the both-
ersome symptoms (such as swelling) associated with the premenstrual phase of the
menstrual cycle. Thus, this pill has the potential to improve women’s quality of life.27
There is some evidence that a triphasic oral contraceptive may be effective for
some of the symptoms of PMS.28 Premenstrual breast pain and bloating were signifi-
cantly reduced with triphasics, but there were no beneficial effects for any of the
mood symptoms.

GnRH analogues

The administration of GnRH analogues, either as depot injection or nasal spray, can
produce anovulation resulting in medical oophorectomy. GnRH analogues cause pitui-
tary desensitization to GnRH by downregulation of GnRH receptors. Consequently,
there is a reduction in the secretion of sex hormones (luteinizing hormone and folli-
cle-stimulating hormone), and, eventually, anovulation is induced. There is some evi-
dence to show that GnRH analogues are more efficacious for the physical symptoms
of PMS than the behavioural symptoms.29 It is used clinically for short-term therapy
as significant trabecular bone loss and menopausal symptoms occur after 6 months
of therapy. The addition of add-back HRT with tibolone prevents these side-effects.
A meta-analysis has demonstrated that the efficacy of GnRH analogues is not dimin-
ished by add-back tibolone and this combination may permit prolonged therapy.29
GnRH analogue therapy will help to identify women with severe PMS who would
benefit from bilateral oophorectomy.
 Hormonal management of premenstrual syndrome 255

Danazol

Danazol has androgenic and antigonadotrophic properties. It is used in gynaecology

for the treatment of endometriosis, fibroids, menorrhagia and other menstrual dis-
orders such as PMS. Danazol has been shown to be of benefit in the treatment of
PMS and cyclic mastalgia when given in doses of 400 mg or 200 mg continuously.30–32
Danazol is thought to produce benefit by suppressing ovulation and eliminating hor-
monal cyclicity.31 There are risks associated with long-term use of danazol. Although
osteoporosis does not seem to be a risk, danazol causes significant masculinizing
side-effects such as hirsutism, weight gain and change of voice.33 As a result, it is
not currently licensed for use in PMS. Some studies have investigated the benefit
and risks of danazol given in the luteal phase alone. The largest of these studies
was by O’Brien and Aukhalil, and used 200 mg danazol in the luteal phase alone.
This regime was not found to be effective in the treatment of general symptoms
of PMS, but it was very effective in the treatment of premenstrual mastalgia with
only a few side-effects.33

Bromocriptine

Bromocriptine is a dopamine agonist with the ability to reduce prolactin levels. It has
been shown to be effective for the treatment of premenstrual mastalgia. The exact
mechanism of action is not fully understood. It has been suggested that prolactin-
related fluid retention in the breast may be the cause of pain in women who suffer
with mastalgia.34 Some studies have shown that bromocriptine improves non-breast
symptoms such as oedema, bloating, weight gain, depression, insomnia, anxiety and
irritability.35–39 However, this benefit has not been shown consistently across studies.

Spironolactone

Spironolactone is an aldosterone receptor antagonist that is used medically as a potas-

sium-sparing diuretic and an antihypertensive. Some studies have suggested that spiro-
nolactone may have a role in the treatment of PMS. Spironolactone has been shown to
improve the premenstrual mood index when given premenstrually at a dose of 100 mg
daily.40,41 Furthermore, general bloating42,43, irritability, depression, breast tenderness,
swelling and sweet craving44 were reduced with the use of spironolactone compared
with placebo in some studies. However, another study demonstrated no improvement
in any symptoms of PMS with spironolactone compared with placebo.45 As a result,
the benefit of spironolactone as a treatment for PMS is controversial due to inconsis-
tent findings in studies.

NON-HORMONAL MANAGEMENT OF PMS

Antidepressants

SSRIs, such as fluoxetine, sertraline, citalopram and paroxetine, have been shown to
be very effective in the management of both physical and behavioural symptoms of
PMS.46–51 The benefit of SSRIs can be observed in the first month of commencing
therapy. Similarly, there is a rapid return of symptoms when SSRIs are stopped. SSRIs
can be taken continuously or intermittently (during the luteal phase alone) with
256 Sa’adatu B. Usman et al

similar benefit.49,51 It is important to note that SSRIs are not licensed in the UK for
the treatment of PMS.
Although less effective than SSRIs, other antidepressants such as bupropion,
clomipramine, nortriptyline and desipramine have also been shown to benefit some
symptoms of PMS.52,53

Dietary supplements

Vitamin B6 in combination with magnesium has been shown to reduce the anxiety
symptoms of PMS.54 Calcium supplementation has been demonstrated to be of benefit
for symptoms such as water retention, food craving and pain.55

Cognitive behavioural therapy

There is some evidence that cognitive behavioural therapy can reduce the negative
impact of PMS and this effect is maintained over time.56

Herbal remedies

A study has shown that the extract of the Agnus cactus fruit (Vitex agnus castus)
provided significant benefit in women with PMS.57 Evening primrose oil only appears
to be effective in the management of cyclical premenstrual mastalgia.58

Complimentary therapy

For very mild symptoms of PMS, aerobic exercise and relaxation can produce some
benefit.59,60 However, there are no controlled trials on the benefit of these treatment
modalities.

Surgery

Hysterectomy with bilateral oophorectomy or bilateral oophorectomy is a cure for

PMS, but this is rather invasive and rarely justified. Surgery is reserved for severe cases
of PMS in which other medical treatments have failed to provide any benefit. Although
rarely performed, it has been shown that surgery in the form of total abdominal hys-
terectomy and bilateral salpingo-oophorectomy with appropriate HRT is an extremely
effective and well-accepted permanent cure for PMS.61

SUMMARY

The exact pathophysiology of PMS is unknown but ovulation has to occur for symp-
toms to develop. Therefore, ovarian hormones are thought to be responsible for
causing PMS. GABA and serotonin pathways in the central nervous system have
also been implicated in the aetiology of PMS. Treatment strategies involve hormonal
manipulation, usually to induce anovulation, or targeting the response systems in the
brain. Correct diagnosis of PMS is vital to its management. More research is needed
to clarify the efficacy of some of the treatment modalities for PMS such as proges-
terone, progestogens and spironolactone. Some of the hormonal treatment options
that have been shown to be of benefit in PMS are oestrogen, GnRH analogues and
 Hormonal management of premenstrual syndrome 257

danazol. The benefit of the COCP has been difficult to establish due to different
progestins used in each COCP. At present, evidence suggests that drospirenone-
containing COCPs provide some benefit in PMS. Bromocriptine and luteal-phase
danazol have been shown to benefit breast symptoms but they fail to show consis-
tent benefit for non-breast symptoms. A recent systemic review on progesterone
treatment in PMS showed that it is neither effective nor ineffective. As a result,
it is not possible to advocate or discourage its use in PMS. SSRIs have been shown
to be efficacious in the management of PMS but are not licensed for use in PMS in
the UK at the moment.
Research is needed to identify subgroups of women that will benefit from specific
treatment modalities. This will help to tailor management of women with PMS accord-
ing to their symptoms.

Practice points

 for the diagnosis of PMS, symptoms should be confirmed prospectively by daily

rating in at least two consecutive menstrual cycles
 progesterone is licensed for the treatment of PMS although there is no evi-
dence that it is effective
 oestrogen is effective in suppressing ovulation and reducing symptoms
 local progestogens should be used to protect the endometrium when using
oestrogen to treat PMS in order to prevent the re-introduction of PMS
symptoms
 GnRH analogues should not be used for more than 6 months unless add-back
tibolone is used
 GnRH analogues can be used to identify sufferers of PMS that will benefit from
bilateral oophorectomy
 danazol therapy causes significant masculinizing side-effects
 luteal-phase danazol and bromocriptine are only effective for breast symptoms
 SSRIs are very effective treatment for PMS, although they are not licensed for
this use
 surgery should be reserved for severe cases of PMS in which medical treatment
has been ineffective

Research agenda

 research into the neuro-endocrine biology of PMS, particularly its genetic basis,
molecular psychiatric aspects and functional imaging
 a re-appraisal of the aetiology theories that have been disregarded in the past
when conclusions were based on loosely defined criteria
 a re-appraisal of the treatment techniques that have been disregarded in the
past when conclusions were based on loosely defined criteria
258 Sa’adatu B. Usman et al

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