Hormones and Mood : PMS and PMDD

The week before the period begins can be a difficult one emotionally for many women.  Different types of mood changes, as well as a range of physical symptoms can occur.  There have been difficulties for many years in finding the hormonal alterations which lead to premenstrual emotional symptoms.  However, the study of neuroendocrinology has uncovered information which indicates that hormones can very much affect our moods.

Premenstrual Syndrome (PMS) is defined as a collection of physical, psychological, and emotional symptoms which occur only during the luteal phase of the menstrual cycle and are of sufficient severity to interfere with some aspects of life. Premenstrual Dysphoric Disorder (PMDD) has a similar cyclical timing to PMS, but mood symptoms predominate and are severe. PMDD often interferes with the sufferer’s ability to function in her social or occupational life. The main symptoms are intense irritability, anxiety, and depression. Although it may contain some of the physical symptoms of PMS (such as bloating, cravings, fatigue, headaches) the symptoms are primarily related to mood. In both cases, symptoms resolve shortly after the onset of the menstrual period.

We have long known that the pituitary gland, the “master gland” is controlled by the hypothalamus in the brain. We now know that hormones produced by the glands such as the ovaries, testes, and adrenal (such as estrogen, progesterone, and testosterone) have effects on brain chemistry through different molecular mechanisms.

Hormones can affect the levels of neurotransmitters in the brain.   In addition to this, there are special hormones known as neuroactive steroids which are synthesized in the brain or central nervous system from other hormones.  These hormones powerfully and rapidly cause changes in brain function.

Hormones and the Menstrual Cycle

Estrogen and Mood

Mood symptoms of PMS and PMDD develop due to the shift in hormone levels related to ovulation.  It is well known that serotonin levels influence the mood, and estrogens have been found to increase serotonergic activity by increasing serotonergic receptors, transport and uptake.   Estrogen decreases after ovulation and then again at the end of the cycle just prior to the period and this is very likely to be one of the triggering causes of PMS and PMDD mood changes.

Progesterone and Mood

Several studies had initially shown no correlation between total progesterone and mood changes of PMS, however knowing that a large shift in progesterone correlates with the stage in the luteal phase when symptoms begin has led to more investigation in this area.

In the brain, ovary and adrenals, progesterone is converted to a neurosteroid called allopregnanolone, also known as tetrahydroprogesterone.  This hormone has been discovered to exert profound effects on mood and mental function.   A 2001 study found a relationship between low levels of allopregnanolone and severe symptoms of PMS and PMDD.  Another study found that commonly prescribed antidepressant medications such as fluoxetine (Prozac)  may in part work through increasing levels of allopregnenalone in the brain.

This specific type of progesterone may be of much interest to those who suffer specifically from premenstrual anxiety.  Allopregnanolone enhances the activity of GABA, the chief inhibitory neurotransmitter in the brain and it is through this mechanism that it exerts its effects on reducing anxiety.  In those women who have lower allopregnanolone levels, the activity of GABA would be reduced, leading to higher levels of anxiety or higher response to stress at the premenstrual time.  Lower levels of allopregnanolone may theoretically be caused by lower activity of the enzymes which create it, 5α reductase and  3α-hydroxysteroidoxidoreductase.  This may be partly genetic in onset (the first gene linked to estrogen in PMDD was discovered in 2007, none have yet to be discovered for allopregnanolone but research on this is in its beginnings).

Integrative Treatments for PMS and PMDD

In integrative medicine, there are two basic things to consider before deciding on treatment for luteal phase mood disorders.  Firstly, are the PMS/PMDD symptoms more akin to anxiety or to depression?  In those who exhibit more of a depressive syndrome, estrogen and serotonin are playing more of a role.  In patients who experience more anxiety and stress symptoms, it is low levels of progesterone/allopregnanolone  which cause symptoms.  It is important to consult your physician before starting any treatment, as specific therapies listed below may have interactions or side effects and use requires professional supervision.

Considerations for women experiencing more depressive symptoms would be :  St John’s wort.  This therapy has been studied and shown to have benefit for patients with PMS and PMDD.  Another consideration would be 5-HTP, which has not been specifically studied clinically for PMS, but does have promising evidence in the treatment of serotonin mediated depressive symptoms.

For patients in the category of anxiety, we must consider that the condition may be arising from either low progesterone, or from poor conversion of progesterone to allopregnanolone.  I would suggest salivary profiling to determine if total progesterone levels are low.  First line treatment options for women with low overall progesterone could include Vitex agnus castus throughout the cycle and vitamin B6.  This would aim to establish healthy corpus luteum function (and thereby increase progesterone) through pituitary regulation. Studies have shown that increasing progesterone levels increases allopregnanolone in the brain.  To reduce symptoms of anxiety : passionflower (which binds to benzodiazapene sites) or GABA can be prescribed to help modulate the reduced action of GABA. For many women, this condition is more evident in the late luteal phase where progesterone levels begin to drop, and therefore a targeted anti anxiety protocol can be used for these few days with a focus on the GABA receptors. In severe cases where progesterone is measured to be low through the luteal phase, a carefully titrated cyclic dosage of bio-identical progesterone can be prescribed by a physician.

In addition, for both types of PMS/PMDD discussed here, calcium and magnesium are important and effective therapies. Abnormal cellular and serum levels of these minerals have been linked to increased PMS mood symptoms.

With therapies targeted to the patient’s individual hormonal picture, PMS and PMDD can be managed for most women, and quality of life can be very much improved.

References

De Berardis et al. Treatment of premenstrual dysphoric disorder (PMDD) with a novel formulation of drospirenone and ethinyl estradiol. Ther Clin Risk Manag. 2007 August; 3(4): 585–590.

Eriksson O, Wall A, Marteinsdottir I, et al. Mood changes correlate to changes in brain serotonin precursor trapping in women with premenstrual dysphoria. Psychiatry Res. 2006 Mar 31;146(2):107-16. Epub 2006 Mar 2

Girdler SS, Straneva PA, Light KC, et al. Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder. Biol Psychiatry. 2001;49:788–97

Halbreich U, Rojansky N, Palter S, et al. Estrogen augments serotonergic activity in postmenopausal women. Biol Psychiatry. 1995;37:434–41.

Kaura V, Ingram CD, Gartside SE, et al. The progesterone metabolite allopregnanolone potentiates GABA(A) receptor-mediated inhibition of 5-HT neuronal activity. Eur Neuropsychopharmacol. 2006 in press

Christine E. Marx, Lawrence J. Shampine, Rahul T. Khisti, William T. Trost, Daniel W. Bradford, A. Chistina Grobin, Mark W. Massing, Roger D. Madison, Marian I. Butterfield, Jeffrey A. Lieberman, A. Leslie Morrow, Olanzapine and fluoxetine administration and coadministration increase rat hippocampal pregnenolone, allopregnanolone and peripheral deoxycorticosterone: Implications for therapeutic actions, Pharmacology Biochemistry and Behavior, Volume 84, Issue 4, Neuroactive Steroids, Neurotransmitters’ Function and Neuropsychiatric Implications, August 2006, Pages 609-617

P Monteleone, S Luisi, A Tonetti, F Bernardi, AD Genazzani, M Luisi, F Petraglia, and AR Genazzani Allopregnanolone concentrations and premenstrual syndrome. European Journal of Endocrinology, Vol 142, Issue 3, 269-273

Rapkin et al. Progesterone Metabolite Allopregnanolone in Women With Premenstrual Syndrome. Obstetrics & Gynecology. 90(5):709-714, November 1997.

Susan Thys-Jacobs, Paul Starkey, Debra Bernstein, Jason Tian and The Premenstrual Syndrome Study Group, Calcium carbonate and the premenstrual syndrome: Effects on premenstrual and menstrual symptoms. American Journal of Obstetrics and Gynecology, Volume 179, Issue 2, August 1998, Pages 444-452

Wang M, Seippel L, Purdy RH, et al. Relationship between symptom severity and steroid variation in women with premenstrual syndrome: Study on serum pregnenolone, pregnenolone sulfate, 5a-pregnane-3, 20-dione and 3a-hydroxy-5a-pregnan-20-one. J Clin Endocrinol Metab. 1996;81:1076–82

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Black cohosh may reduce side effects of Clomid / clomiphene

Clomid is one of the most commonly used pharmaceuticals in the treatment of fertility concerns today.  It is often the first therapy used.  Clomid (also known as clomiphene) binds to estrogen receptors, inhibiting the action of estrogen (which is produced by developing follicles) on the hypothalamus in the brain.   As a result, the pituitary gland perceives estrogen levels to be low (when they actually are not), and it responds by producing increased levels of both LH and FSH.  This causes increased follicle production by the ovaries, and stimulation of ovulation.pregnancy with clomid therapy

As effective as this therapy can be at inducing ovulation, studies have indicated fertility specific side effects of clomiphene, many of which are caused by its antagonism to estrogen. The major fertility related side effects are: 1) thinning of the endometrial lining and 2) reduction of cervical mucous required for entry of sperm into the uterus.

One of the isomer forms of clomiphene has a slow excretion rate from the body (it can take more than 6 weeks to be excreted).  If clomiphene therapy is used for longer than two months, side effects can be more pronounced, resulting in greater thinning of the endometrial lining which is needed for healthy implantation. In women over 40, endometrial lining thins naturally, and perhaps this is why clomiphene is often not an effective treatment in this group of patients.

For many women, the ovulation induction produced by this medication can be the answer to ovulation difficulties however therapy often must be stopped after a short period due to side effects over time. Estrogen therapy has been studied in conjunction with Clomid presumably to offset the anti-estrogenic effects of the medication, with mixed results.  Some studies have found giving additional estrogen to women to be helpful, and others have found it to be of no benefit.

Recently, two studies have been completed on combining black cohosh (also known as Cimicifuga racemosa) with clomiphene in patients seeking treatment for infertility.  Cimicifuga is a botanical therapy, often used in womens health to treat menopausal conditions such as hot flashes.  Estrogenic effects of black cohosh remain highly debated, with early studies indicating that it  directly affects estrogen receptors, and more recent studies showing that the effect of the plant may occur from an entirely different mechanism.  Without yet knowing the exact mechanisms through which black cohosh works, several convincing studies have indicated it to be beneficial in the clinical treatment of hormonal disorders.  A recent study has indicated that black cohosh may reduce proliferative effects of estrogens on tissues, which is in line with the effect of many phytoestrogens, however the mechanism for this remains to be elucidated.

In the first study conducted in 2008, black cohosh was found to significantly increase estradiol and LH concentrations in patients taking clomiphene therapy.   Endometrial thickness, serum progesterone and clinical pregnancy rate in patients were significantly higher in the black cohosh group as compared to control.

The second study was completed in 2009. In this study of patients taking clomiphene, black cohosh given in the follicular phase was compared to estrogen therapy, presumably in order to determine which could reduce side effects more effectively. The black cohosh group needed significantly fewer days for healthy follicular development, had a thicker endometrial lining and had higher estradiol concentration at the time of HGG ovulation trigger when compared to the estrogen replacement therapy group.  Clinical pregnancy rate was 14.0% in the estrogen replacement group versus 21.1% in the black cohosh group. Although this did not reach clinical significance, it appears that the black cohosh group did display many benefits overall when compared to the estrogen replacement group. When results from the previous study are also considered, it appears that this therapy may warrant serious consideration and further study for those undergoing clomiphene treatment.

More studies will need to be conducted in order to determine the mechanisms of this herbal medicine’s benefits for patients undergoing modern assisted reproductive technology therapies.

References:

Homburg, I.  Clomiphene citrate—end of an era? a mini-review.  Human Reproduction 2005 20(8):2043-2051

Insler, V MB, BCh; Zakut, H MD; Serr, D M MB, ChB. Cycle Pattern and Pregnancy Rate Following Combined Clomiphene-Estrogen Therapy. April 73 (4) 4

Massai et al.  Clomiphene citrate affects cervical mucus and endometrial morphology independently of the changes in plasma hormonal levels induced by multiple follicular recruitment.  Fertil Steril. 1993 Jun;59(6):1179-86

Osmers et al. Efficacy and Safety of Isopropanolic Black Cohosh Extract for Climacteric Symptoms. Obstetrics & Gynecology:  May 2005 – Volume 105 – Issue 5, Part 1 – pp 1074-1083

Sandro Gerli, Hossein Gholami, Antonio Manna, Antonio Scotto Di Frega, Costantino Vitiello, Vittorio Unfer, Use of ethinyl estradiol to reverse the antiestrogenic effects of clomiphene citrate in patients undergoing intrauterine insemination: a comparative, randomized study, Fertility and Sterility, Volume 73, Issue 1, January 2000, Pages 85-89

Shahin AY, Ismail AM, Shaaban OM. Supplementation of clomiphene citrate cycles with Cimicifuga racemosa or ethinyl oestradiol–a randomized trial. Reprod Biomed Online. 2009 Oct;19(4):501-7.

Shahin, Ahmed Y.1; Ismail, Alaa M.1; Zahran, Kamal M.1; Makhlouf, Ahmad M.1 Adding phytoestrogens to clomiphene induction in unexplained infertility patients – a randomized trial. Reproductive BioMedicine Online, Volume 16, Number 4, April 2008 , pp. 580-588(9)