Diagnosis and Treatment of Premenstrual Syndrome Part Three

Diagnosis and Treatment of Premenstrual Syndrome Part Three by Jeffrey Dach

Gilda is a 42 year old mother of three, works as a Zumba instructor, and has been doing well on her 2 grains of natural thyroid for Hashimoto’s thyroid disease. Lately, Gilda’s PMS symptoms have been worsening. Note: PMS is premenstrual syndrome. Gilda’s symptoms occur during the last two weeks of the menstrual cycle (luteal phase) when she reports anxiety and irritability, breast tenderness, and headaches. In the past, Gilda has always been very regular, with 28 day menstrual cycles, however, recent laboratory testing on day 19 of the cycle showed a normal estrogen (estradiol) level, 170 pg/ml, with a low progesterone level of 0.1 ng/ml. The low progesterone indicates anovulation and “estrogen dominance”. Gilda was started on progesterone topical cream 50 mg for days 12-26 of the menstrual cycle. A few months later, I received this email from Gilda:

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Dear Dr. Dach,
Hello and good morning, I hope everything is well with you all! My gynecologist asked me to have the composition of the progesterone cream I am using, the reasons I am using it, and for how long I will be using it.

Thank you!
from Gilda.
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Dear Gilda,

The natural progesterone dosage is 50 mg per day as a topical cream. Progesterone is a treatment for PMS associated with anovulatory cycles. The length of treatment is yet to be determined. If there are any other questions, I am happy to discuss with your doctor. Give them my office number to call me: 954-792-4663.

regards, Dr. D.

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Header Image: Study for “A Sunday on La Grande Jatte” Date 1884. Georges Seurat (1859–1891). oil on canvas. Metropolitan Museum of Art online collection (The Met object ID 110002111) Source: art database. Public Domain. Coutesy of Wimimedia Commons.

Symptoms of PMS

It is not unusual for mainstream OB/Gyne doctors to have no knowledge of the use of natural progesterone for PMS. It may even seem foreign to them. OB/Gyne medical training and educational journals tell them natural progesterone doesn’t work for PMS, so don’t even think about it. For the mainstream OB/Gyne doctor, first line treatments for PMS are SSRI antidepressants and oral contraceptive pills (OCP’s). Although both are effective, their adverse side effects preclude their use, except under the most extreme circumstances. For the vast majority of women, effective safer measures are available as described in this newsletter. Treatment strategy is important since PMS affects more than half of reproductive age women worldwide. The common symptoms during the luteal phase of menstrual cycle are: breast tenderness and pain, weight gain, bloating, headache, mood swings, depression, anxiety, anger, and irritability. (1)(24)(31-33)

Note: follicular phase is the first 11 days before ovulation. Luteal phase is the last 14-17 days after ovulation.

Cyclic Progesterone for PMS

In 1953, the early pioneer in the use of natural progesterone for PMS was Katharina Dalton, a British MD who coined the term “PMS” and ran a women’s PMS clinic for more than 40 years using injectable progesterone (25 mg) with considerable success for PMS symptoms. I wonder what Dr. Dalton’s thoughts were in 1994 when PMS was renamed a mental disorder called premenstrual dysphoric disorder (PMDD), by the American Psychiatric Association. (161)

Initially, Dr. Dalton used injectable progesterone, and later when available, vaginal suppositories with starting dosage 400 mg twice a day (800 mg/day). Dr. Dalton’s 1953 paper on PMS in the British Medical Journal is a classic, describing the use of injectable progesterone (25 mg) and oral progestins (ethisterone) for PMS in 83 cases. Dr. Dalton writes:

All the cases had attacks of various symptoms, which occurred during the premenstrual phase, during menstruation or ovulation, or at the time of a missed period, and all cases were symptom-free at other times. All cases included in the series had experienced attacks during each of the last three menstrual cycles; thus any chance coincidence between the attack and menstruation was eliminated…patients were asked to keep a calendar…Symptoms: Headache. nausea, irritability, depression , joint pain, pitting edema, asthma, epilepsy, mastalgia, acne, eczema, glossitis…Is Water Retention the Cause of the Syndrome ? That the symptoms are due to water retention is strongly suggested by the oliguria and gain in weight which announces their arrival and the diuresis and loss of weight which accompanies their relief at, or soon after, the onset of menstruation…the trouble was not so much a high level of oestradiol as a lack of antagonism by progesterone…the cause of the syndrome is an abnormally high oestradiol/progesterone ratio…painful breasts, so common a feature of the syndrome, are due to a high oestrogenic level…The results with intramuscular progesterone in 61 cases were more satisfactory- (83.5%) became free from symptoms, 4 (6.6%) improved, and 4 (6.6%) obtained no relief…Treatment with a progestogen is almost invariably successful. In mild cases relief is usually obtained by the oral administration of ethisterone in a dosage of 25 mg. twice daily during the second half of the menstrual cycle. A larger proportion of patients can be relieved by the intramuscular injection of progesterone, 25 mg. on alternate days during the same phase of the cycle. Such cases are more effectively treated, with less labour for the patient, by the implantation of progesterone, which remains effective for many months. (14)

Dr. Dalton found a connection between PMS symptoms, crime and suicide, finding half of all female crimes and suicides in England between 1950 and 1970 occurred in the four days before menstruation, typically the worse “PMS days” of the menstrual cycle. (15)

However, Dr. Dalton’s success with progesterone for PMS was met with opposition from the medical community who failed to replicate her success, citing numerous RCT’s (randomized controlled trials) showing progesterone ineffective for PMS. This opposition by conventional medicine continues to the current day. (12-16)(25-30)

Dr. Dalton’s response to criticism from the mainstream medical system is the dosage of the progesterone was much too low to achieve success. Because of receptor cross-talk, low doses of progesterone up-regulate estrogen receptors, thus aggravating rather than calming estrogen dominance symptoms, making all the PMS symptoms worse. This is one of the pitfalls of using progesterone for PMS commonly found in the conventional medicine approach. Many PMS patients require higher doses to achieve adequate blood levels of progesterone as described by Dr. Phyllis Bronson below. Both Dr. Dalton and Dr Bronson’s conclusions and views were validated in 2019 by Dr. Chutima Roomruangwong in a study of 21 women with symptoms of PMS, and 21 women without symptoms (controls). Dr. Roomruangwong found that PMS symptoms could be predicted by lower steady state levels of progesterone, as well the declining levels of progesterone during luteal phase. (158-160)

Positive Studies on Use of Progesterone

A number of positive studies on the use of progesterone for PMS were largely ignored. For example, in 1985, Dr. L. Dennerstein ran four month double blind crossover study of progesterone for PMS using 300 mg of micronized oral progesterone for the luteal phase (days 14-24) of the menstrual cycle (100 mg with breakfast, and 200 mg at bedtime). Dr. Dennerstein writes:

This study showed that an oral formulation of micronized progesterone was effective in alleviating many premenstrual complaints including those of anxiety, stress, depression, hot flushes, swelling, and water retention. (19)

In 2017, Dr. Olha Horbatiuk from Ukraine studied 37 premenopausal women with preserved menstrual cycles suffering from severe PMS, compared to 32 controls without PMS. The women were treated with sublingual micronized progesterone for days 11-25 of the menstrual cycle. Full resolution of PMS symptoms were noted in 86 percent of patients, writing:

86.5% of all women of the main group were observed to have had full regression of severe PMS clinical effects, while 13.5% of all women suffering from severe PMS and who were within the decompensated stage were observed to have a decrease in PMS symptoms. (162)

Phyllis Bronson PhD, Experience Using Progesterone for PMS

In 2002, Dr. Phyllis Bronson studied the use of progesterone in women suffering from PMS and mood disturbance during luteal phase of menstrual cycle. Dr. Bronson found success with topical progesterone 100 mg applied twice a day (200 mg/day). Again, very similar to Dr Katharina Dalton’s protocol, Dr. Phyllis Bronson found higher doses of progesterone effective with some patients requiring up to 600 mg per day of topical progesterone. Dr. Bronson ran frequent serum estradiol and progesterone levels, finding patients felt best when progesterone levels reach at least 4 ng/ml and at the same time, estrogen (estradiol) below 100 pg/ml. In some cases, relief of mood symptoms requires progesterone levels of 8-15 ng/ml. Dr. Bronson found that estrogen is neuro-excitatory, and high levels of estrogen may predispose to anxiety and panic attacks. Natural progesterone, on the other hand, is neuro-inhibitory, with calming effects. Dr. Phyllis Bronson writes:

Interestingly, for subject 2, all her adult life she had thought she was prone to significant depression. She had been treated with psychotropic medications, specifically Paxil and Prozac with little relief. After treatment with natural progesterone for fifteen months, from October of 1996 until December of 1997, she finally felt really well premenstrually for the first times in years. This has continued but with some variations…She reported feeling best at times when progesterone levels came up at least to 4 ng/ml, and estrogen levels decreased below 100 pg/ml…After the introduction of micronized progesterone, in the form of transdermal progesterone cream, pre-menstrual tension has essentially been obliterated….we are seeing this trend show up in many more subjects not in the original study but being seen at our clinic…The evidence points toward the premise that in anxiety prone women, when progesterone levels are low relative to estrogen, these subjects feel tense and irritable, and exhibit other criteria of general anxiety. Relief of these symptoms is generally seen when progesterone is measured at 8-15 ng/ml. The mood changes were qualified as follows. As the progesterone levels rose gradually, most symptoms of acute anxiety disappeared. Chronic symptoms took longer to dissipate, although they too diminished over time. The subjects also reported that if they were not diligent about using progesterone, symptoms recurred…I refer here to the recent work of John Lee. He is the pioneer in the use of natural progesterone…The women seen repeatedly reported that the changes in mood happened congruent with elevated serum hormone levels of progesterone, usually accompanied by a drop in high estrogen levels! Early in our research these changes did not occur at physiologic doses (as promoted by Dr. John R. Lee) or when low dose progesterone was used at 1.6% [16 mg per gram].(8-11)

The Safety of High Dose Progesterone

Progesterone levels in pregnancy are many times higher than obtainable with the use of topical, vaginal or oral progesterone indicating safety of use of high doses for PMS. In 2012, Dr. Pratap Kumar notes progesterone levels in third trimester may reach 200 ng/ml, writing:

When the pregnancy reaches term gestation, progesterone levels range from 100-200 ng/ml and the placenta produces about 250 mg/day. (164)

Chaste Tree: Vitex Agnus Castus for PMS

Perhaps the most successful botanical extract for PMS is called Chaste Tree or Vitex Agnus used for centuries in folk medicine for menstrual disorders. In 2006, Dr. Tori Hudson described Vitex Agnus as “the single most important plant for the treatment of premenstrual syndrome”. (20-22)

Vitex Consumption by Wild Female Chimpanzees

In 2008, Dr. Melissa Emery Thompson studied urinary hormone levels in wild female chimpanzees consuming Vitex fischeri, finding consumption of Vitex fruit caused an abrupt and dramatic increase in progesterone levels, writing:

V. [Vitex] fischeri consumption was associated with an abrupt and dramatic increase in urinary progesterone levels of female chimpanzees to levels far exceeding the normal range of variation. Female estrogen levels were not significantly impacted, nor were male testosterone levels.(42)

Dopamine like Compounds in Vitex for PMS

In 2003, Dr. Wolfgang Wuttke reviewed the pharmacology and clinical indications for Chaste Tree (Vitex) finding widespread use of Vitex for PMS symptoms. Dr. Wuttke found the fruit extract contains dopaminergic compounds, which are perhaps the most clinically useful for treatment of premenstrual mastodynia (breast pain, tenderness) and PMS (premenstrual syndrome) symptoms, writing:

Extracts of the fruits of chaste tree (Vitex agnus castus = AC) are widely used to treat premenstrual symptoms. Double-blind placebo-controlled studies indicate that one of the most common premenstrual symptoms, i.e. premenstrual mastodynia (mastalgia) is beneficially influenced by an AC extract. In addition, numerous less rigidly controlled studies indicate that AC extracts have also beneficial effects on other psychic and somatic symptoms of the PMS. Premenstrual mastodynia is most likely due to a latent hyperprolactinemia, i.e. patients release more than physiologic amounts of prolactin in response to stressful situations and during deep sleep phases which appear to stimulate the mammary gland. Premenstrually this unphysiological prolactin release is so high that the serum prolactin levels often approach heights which are misinterpreted as prolactinomas. Since AC extracts were shown to have beneficial effects on premenstrual mastodynia serum prolactin levels in such patients were also studied in one double-blind, placebo-controlled clinical study. Serum prolactin levels were indeed reduced in the patients treated with the extract. The search for the prolactin-suppressive principle(s) yielded a number of compounds with dopaminergic properties…almost identical in their prolactin-suppressive properties than dopamine itself. Hence, it is concluded that dopaminergic compounds present in Vitex agnus castus are clinically the important compounds which improve premenstrual mastodynia and possibly also other symptoms of the premenstrual syndrome. (45-47)

In 2017, Dr. Wolfgang Wuttke again studied Vitex as a treatment for PMS, finding breast pain and tenderness symptoms of PMS was due to prolactin release by the pituitary which also is the explanation for anovulatory cycles commonly seen. The elevated prolactin levels from pituitary prolactin release is inhibited by dopamine-like compounds in Vitex, thus restoring ovulation and eliminating the breast pain and other symptoms of PMS. Dr. Wolfgang Wuttke writes:

The dried fruits of the chaste tree Vitex agnus castus (VAC) were traditionally used by monks as a substitute for pepper and was therefore also called Monk’s pepper. For the last 50 years it is commercially provided for the treatment of premenstrual symptoms, particularly to prevent premenstrual mastodynia (mastalgia)…A number of placebo controlled studies gave proof that extracts of VAC had beneficial effects on premenstrual breast pain. This breast sensation is induced by latent hyperprolactinemia which is characterized by secretory episodes of prolactin release by the pituitary in response to stress and deep sleep phases. This latent hyperprolactinemia induces…a corpus luteum insufficiency which is a common reason for infertility [anovulation]…it is well accepted that prolactin release can be reduced by dopamine and dopaminergic drugs. The efficacy of VAC extracts to ameliorate prolactin induced premenstrual mastodynia was therefore suggestive that VAC may contain dopaminergic compounds. Indeed, a number of diterpenes were identified that bound to recombinant Dopamine receptors of the 2 subtype (D2 receptors) which are present in pituitary lactotropes and which mediate the inhibitory effects of dopamine and dopaminergic drugs on pituitary prolactin release. Consequently, prolactin release in vitro from dispersed pituitary cells and in vivo in rats and postmenopausal women was inhibited by VAC 1095. Placebo controlled studies proved also the efficacy of VAC extracts to ameliorate premenstrual symptoms. In several placebo-controlled studies a clear relation between reduction of breast pain and reduction of serum prolactin levels could be established. In addition VAC extracts was also highly effective in women suffering from fibrocystic mastopathy. In many of these women serum prolactin levels were also elevated and reduced by VAC extracts…The results from all trials suggested that VAC extracts ameliorated premenstrual symptoms including mastodynia, premenstrual dysphoric disorder and latent hyperprolactinemia. Cystic mastopathy and sterility due to corpus luteum insufficiencies were also beneficially influenced. Adverse events with VAC were mild and generally infrequent. (48-52)

Vitex Treatment for Hyperprolactinemia

In 2020, Dr. Naiyereh Haerifar studied 105 women of reproductive age with elevated prolactin levels. The women were divided into three groups and treated with bromocriptine, Dostinex [cabergoline], or Vitagnus (Vitex) over 4 months. Note: bromocriptine and cabergoline are dopaminergic drugs (dopamine D2 receptor agonists), commonly used to treat hyperprolactinemia, usually caused by pituitary adenoma. The women treated with Vitex had a significant increase in estradiol and progesterone levels, and a decrease in prolactin levels. Dr. Naiyereh Haerifar writes:

The results further revealed that the amounts of estradiol in the Vitagnus group had a significant increase compared to other groups (P < 0.05)…Eventually, the effect of the Vitagnus tablet on progesterone was remarkable compared to the other two medications in the 2nd and 3rd cycles. Conclusions: Similar to other drugs, Vitagnus has a significant effect on the amount of prolactin and sex hormones and thus can be successfully used in treating hyperprolactinemia. Finally, reductions in endometrial thickness were significant in the Vitagnus group [this is a progesterone effect which thins the endometrial stripe visible on pelvic sonogram] compared to the other two groups. (44)

Vitex Meta-Analysis of 17 RCT’s by Dr. Verkaik

In 2017, Dr. Saskia Verkaik did a meta-analysis of 17 RCT’s of Vitex for PMS, finding efficacy greater then placebo, and efficacy equal to oral contraceptives, and to SSRI antidepressant (fluoxetine) for PMS. In addition, efficacy of Vitex was better than all other herbal extracts and supplements. (50)

The Serotonin Connection – 5HTP for PMS and Mood Disorders

The serotonin precursor amino acid, tryptophan, is converted in the brain to 5HTP (5 hydroxy tryptophan), which is then converted to serotonin, an improtant neurotransmitter. In 2009, Dr. Miles Berger writes:

The behavioral and neuropsychological processes modulated by serotonin include mood, perception, reward, anger, aggression, appetite, memory, sexuality, and attention, among others. Indeed, it is difficult to find a human behavior that is not regulated by serotonin. (163)

Multiple placebo controlled studies have found SSRI antidepressants effective for PMS. Note: SSRI drugs are designed to inhibit serotonin re-uptake by the terminal synapse and increase serotonin concentration at the synaptic cleft. As mentioned above, 5HTP is the precursor to synthesis of serotonin and widely available at the health food store. The next logical thought is why not try oral tryptophan or 5HTP capsules as a safer way to increase brain serotonin levels? In 2021, Dr. İpek Ayhan studied the mechanism of PMS within the brain, pointing out many of the symptoms of PMS are associated with the serotonergic system, and are made worse by tryptophan depletion, writing:

Aggression, impulse control, anxiety, sexual behavior, pain, sleep, and eating difficulties are some of the symptoms of PMS, and these symptoms are associated with the serotonergic system. Some studies demonstrated that tryptophan, a serotonin precursor, has antidepressant properties and that acute tryptophan deficiency exacerbates premenstrual symptoms. (1)(57)

In 1999, Dr. Susanne Steinberg studied the effect of tryptophan on PMS in a RCT over 3 months, finding a beneficial effect on PMS symptoms. 37 PMS patients were given L-tryptophan, 6 grams /day orally, and 34 PMS patients were given placebo. Treatment was given during the luteal phase of the menstrual cycle for four cycles. Dr. Steinberg writes:

Results: The Visual Analogue Scales (VAS) revealed a significant (p 5 .004) therapeutic effect of L-tryptophan relative to placebo for the cluster of mood symptoms comprising the items of dysphoria, mood swings, tension, and irritability. The magnitude of the reduction from baseline in maximum luteal phase VAS-mood scores was 34.5% with L-tryptophan compared to 10.4% with placebo. Conclusions: These results suggest that increasing serotonin synthesis during the late luteal phase of the menstrual cycle has a beneficial effect in patients with premenstrual dysphoric disorder. (67-68)

5-HPT is a more direct precursor to serotonin, and is probably more effective at lower doses when compared to tryptophan, thus 5-HTP is preferable.

Myo-Inositol to Restore Regular Menstrual Cycles and Stop Abnormal Bleeding

For the young female with abnormal uterine bleeding associated with anovulatory menstrual cycles, abnormal uterine bleeding, anemia and PMS symptoms, myoinositol is a safe nutritional supplement shown to be highly effective in restoring ovulation and normalizing the menstrual cycle. In 2024, Dr. Galina Dikke from St. Petersburg, Russia, studied the use of micronized progesterone combined with myoinositol, D-chiroinositol (5:1 ratio) along with a folic acid and manganese in 2,042 women, average age of 30 years, with anovulatory heavy menstrual bleeding and PMS. The women were treated for 6 months, the first three months with progesterone and myoinositol, and the second three months with myoinositol alone. After 6 months, 91 percent of the women achieved normal menstrual cycles with resolution of anemia. Dr. Galina Dikke writes:

Abnormal uterine bleeding (AUB) associated with ovulatory disfunction (OD) [anovulation] is the most common finding among women with chronic AUB, accounting for 57.7% of cases. Oral progestogens are often prescribed for irregular and copious menstruation. However, a course of hormonal rehabilitation after AUB-OD may not be enough. Inositols have been shown to be highly effective in restoring ovulation, normalizing the menstrual cycle. (56-66)

For more on Myo-Inositol, see Myoinositol for PCOS and Hashimoto’s Thyroiditis

Mainstream Use of Progestins for Abnormal, Dysfunctional Uterine Bleeding

Although synthetic progestins such as medroxyprogesterone (MPA) are known to be carcinogenic with increased risk for breast cancer, their use in dysfunctional uterine bleeding (DUB) by mainstream OB/Gyne practice is justified, allowing the patient to avoid hysterectomy. For progestin usage for dysfunctional uterine bleeding, their carcinogenicity is overlooked. (97-118)

Vitamin B6

Vitamin B6 is a cofactor in the synthesis of serotonin from tryptophan and 5HTP, and for the synthesis of dopamine from tyrosine. Consuming vitamin B6, or its biologically active form, P-5-P, pyridoxyl 5-phophate, improves brain production of both serotonin and dopamine. This suggests utility of B6 in PMS and other neuropsychiatric syndromes. A number of studies show taking B6 or P5P provides benefit over placebo for PMS. (82-93)

Cannabidiol (CBD) for PMS

A number of studies and sources suggest CBD useful in ameliorating PMS symptoms. (94-96)

Conclusion:

In my opinion, the use of SSRI antidepressants and oral contraceptives for PMS, althoughconsidered by manstream medicine to be effective, is a misguided form of treatment because of adverse side effects. High dose natural progesterone is safer, and has been shown effective assuming the correct dose is used, and is the preferred treatment. Progesterone is available OTC (over the counter) and as prescription from compounding pharmacies as topical creams, micronized oral capsules or as vaginal suppositories. Also useful are various other natural remedies: Vitex Agnus, Myoinositol, 5-HTP, vitamin B6 (P5P) and CBD.

Free Progesterone Consultation with Carol Petersen at the Wellness by Design Project

Take advantage of a free 15 min. consultation with progesterone expert, Carol Petersen, a compounding pharmacist with three decades of experience with natural progesterone for PMS symptoms. Carol is perhaps today’s version of Katharina Dalton. Carol is a graduate of the University of Wisconsin School of Pharmacy and a Certified Nutritional Practitioner. Left Image Courtesy of Carol Petersen

Click Here to schedule your free 15 minute consultation with Carol. Don’t forget to mention my name.

Click Here for Link to buy Progesterone Products at the Wellness by Design Project.

Progesterone Articles by Carol Petersen

A Tribute to Dr. Katharina Dalton July 10, 2024 by Carol Petersen

Can You Use TOO Much Progesterone? July 10, 2023 by Carol Petersen

PMDD: The Tragedy of Premenstrual Dysphoric Disorder
May 8, 2023 by Carol Petersen

Symptoms of Progesterone Deficiency August 4, 2022 by Carol Petersen

When Women Don’t Like Progesterone January 25, 2022 by Carol Petersen

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Buy Chaste Tree Vitex Agnus from Pure Encapsulations

Buy 5 HTP from Pure Encapsulations

Buy P5P Pyridoxine from Pure encapsulations

Buy Myoinositol Complex from Pure Encapsulations

Buy CBD from Beautiful Earth Organics

Progesterone Products Available OTC:

Buy Over the Counter Progesterone from ONAS:

ONAS Natural progesterone cream / pump (Luna Pro 20%, 200 mg per pump)

Buy Emerita Pro-Gest Cream, 4 oz. tube by Emerita on Amazon

Articles with Related Content:

Progesterone Part One

Progesterone Part Two

All Bioidentical Hormone Articles

Fullscript Reference Sheet on Vitex agnus-castus

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
my blog: www.jeffreydachmd.com

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References: Progesterone for Perimenopause/ PMS

1) Prior, J. C. “Progesterone for Symptomatic Perimenopause Treatment–Progesterone politics, physiology and potential for perimenopause.” Facts, views & vision in ObGyn 3.2 (2011): 109.

Because P4 and E2 complement/counterbalance each other’s tissue effects, oral micronized P4 (OMP4 300 mg at bedtime) is a physiological therapy for treatment-seeking, symptomatic perimenopausal women. Given cyclically (cycle d 14-27, or 14 on/off) in menstruating midlife women, OMP4 decreases cyclic VMS, improves sleep and premenstrual mastalgia.

Progesterone for PMS

BRAIN

Mentions tryptophan and serotonin , other neurotransmitters etc.

1) Ayhan, İpek, et al. “Premenstrual syndrome mechanism in the brain.” Demiroglu Science University Florence Nightingale Journal of Medicine 7.2 (2021): 213-224.

Breast swelling, headaches, nausea, vomiting, diarrhea, edema in the body, weakness, weight gain, decreased concentration, forgetfulness, excessive sleepiness or insomnia, change in sexual desire, feeling alone, depressed mood, irritability, tension, nervousness, anxiety, aggression, and depression-like feelings are the most common symptoms of PMS.[8-14] Symptoms worsen six days before menstruation begins and peak two days before.[9]

Although symptoms are present in 70 to 80% of women, on average, 5% of women have clinically significant and more severe symptoms.[8] The World Health Organization (WHO) estimated that 199 million women suffer from PMS in 2010.[16] During their luteal phase, an estimated 80% of menstruating women around the world experience one or more PMS symptoms.[17] According to another study, roughly 30 to 40% of women of reproductive age suffer from PMS, with 3 to 8% of menstrual women experiencing more severe symptoms.

Premenstrual dysphoric disorder is a depressive disorder that affects functionality, is less common, and is listed in the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5)

Mood symptoms appear during the luteal phase and disappear immediately after menstruation, implying that gonadal steroids (estrogen and progesterone) have a role in PMS pathogenesis.[9]

Combined oral contraceptives (COCs) are used in the treatment of gynecological symptoms of PMS. Increased sensitivity to the high progesterone level that occurs after ovulation, as well as ovulation suppression, has been observed to generate a variety of behavioral and physical premenstrual symptoms. Selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of nervousness and anxiety symptoms.[13] Other reproductive hormones, such as estradiol, testosterone, the adrenal hormones cortisol, and dehydroepiandrosterone sulfate, prolactin, and thyroxine, have similarly failed to differentiate women with PMD from controls in previous studies.[31]

many double-blind randomized controlled trials (RCTs) have failed to demonstrate the efficacy of progesterone supplementation.[32-34]

Currently, the SSRIs in treatment for PMDD are administered with intermittent dosing during the luteal phase.[52,53] However, it is known that SSRIs cause problems in sexual function. Nevertheless, the first-line treatment for PMS symptoms is still serotonergic antidepressants.[10,13,53] Studies are showing that the intermittent use of SSRIs increases the effectiveness of the treatment.[54] In a case report, it was observed that SSRIs used in the treatment of a patient with PMDD after brain injury were not functional in reducing suicidal thoughts and preventing other symptoms. [55] The mechanism by which SSRIs increase central allopregnanolone levels in both rats and humans may include direct stimulation of 3α-hydroxysteroid dehydrogenase (3α-HSD), the enzyme that catalyzes the reduction of 5α-dihydroprogesterone (5α-DHP) to allopregnanolone.[41] Despite the effectiveness of SSRIs in PMDD, more research is needed to understand the underlying mechanism and to evaluate the treatment as a whole, including psychosocial therapies in addition to PMS.

In another randomized controlled trial, PMDD symptoms were significantly reduced when the conversion of progesterone to allopregnanolone was blocked by dutasteride, an 5a-reductase inhibitor.[60]

In one study, it was found that people who took 400 IU or more of vitamin D daily had a reduced prevalence of PMS than those who took less vitamin D.[45] Calcium therapy is also applied as a non-drug treatments in PMDD and PMS.[13] In addition, there are significant similarities between hypocalcemia and PMS symptoms in studies showing that calcium supplementation therapy is effective.[75,76]

2) Rapkin AJ, Akopians AL. Pathophysiology of premenstrual syndrome and premenstrual dysphoric disorder. Menopause Int 2012;18:52-9.

!!!!!!!!!!!!!!!! BEST 2023 Progesterone and the Brain !!!!!!!!!!!!!!!!!!!

3) Stefaniak, Małgorzata, et al. “Progesterone and its metabolites play a beneficial role in affect regulation in the female brain.” Pharmaceuticals 16.4 (2023): 520.

Abstract: Premenstrual dysphoric disorder is a female affective disorder that is defined by mood symptoms. The condition is linked to unstable progesterone concentrations. Progestin supplementation is given in cases of threatened or recurrent miscarriage and for luteal phase support. Progesterone is essential for implantation, immune tolerance, and modulation of uterine contractility. For a long time, the administration of progestins was associated with an unfavorable impact on mood, leading to negative affect, and, therefore, was contraindicated in existing mood disorders. Establishing the role of the natural progesterone derivative allopregnanolone in advances in the treatment of postpartum depression has shed new light on the general pathophysiology of mood disorders. Allopregnanolone directly interacts with gamma-aminobutyric acid type A (GABA-A) receptors even at nanomolar concentrations and induces significant anti-depressant, anti-stress, sedative, and anxiolytic effects. Postpartum depression is caused by a rapid drop in hormones and can be instantly reversed by the administration of allopregnanolone. Premenstrual dysphoric disorder can also be considered to result from insufficient neuroactive steroid action due to low progesterone derivative concentration, unstable hormone levels, or decreased receptor sensitivity. The decrease in progesterone levels in perimenopause is also associated with affective symptoms and an exacerbation of some psychosomatic syndromes.

Bioidentical progesterone supplementation encounters several obstacles, including limited absorption, first-pass effect, and rapid metabolism. Hence, non-bioidentical progestins with better bioavailability were widely applied. The paradoxical, unfavorable effect of progestins on mood can be explained by the fact that progestins suppress ovulation and disturb the endocrine function of the ovary in the luteal phase. Moreover, their distinct chemical structure prevents their metabolism to neuroactive, mood-improving derivatives. A new understanding of progesterone-related mood disorders can translate the study results from case series and observational studies to cohort studies, clinical trials, and novel, effective treatment protocols being developed.

Progesterone derived neuro-steroids

4) Stiernman, Louise, et al. “Emotion-induced brain activation across the menstrual cycle in individuals with premenstrual dysphoric disorder and associations to serum levels of progesterone-derived neurosteroids.” Translational psychiatry 13.1 (2023): 124.

5) Geng, Xiwen, et al. “ShuYu capsule alleviates emotional and physical symptoms of premenstrual dysphoric disorder: Impact on ALLO decline and GABAA receptor δ subunit in the PAG area.” Phytomedicine: international journal of phytotherapy and phytopharmacology 130: 155549.

Progesterone is Neuroprotective – Traumatic Brain Injury

6) Sayeed, Iqbal, and Donald G. Stein. “Progesterone as a neuroprotective factor in traumatic and ischemic brain injury.” Progress in brain research 175 (2009): 219-237.

7) Sofuoglu, Mehmet, Maria Mouratidis, and Marc Mooney. “Progesterone improves cognitive performance and attenuates smoking urges in abstinent smokers.” Psychoneuroendocrinology 36.1 (2011): 123-132.

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Phyllis Bronson
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8) Bronson, Phyllis June. The biochemistry of women at midlife: The interface of hormones and neuroinhibitory amino acids on midlife mood. The Union Institute, 1999.

9) Bronson, Phyllis J. Moods, Emotions, and Aging: Hormones and the Mind-body Connection. Rowman & Littlefield Publishers, 2013.

10) Bronson, Phyllis J. “In Defence of Estrogen.” Journal of Orthomolecular Medicine 22.3 (2007): 147-152.

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Phyllis Bronson 100 mg BID topical progesterone for MOOD Disorder

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11) Bronson, Phyllis J. “Mood Biochemistry of Women at Mid-life.” Journal of Orthomolecular Medicine 16.3 (2001): 141-154.

The clinical trial involved a detailed biochemical study of two women and a less intensive study of two other groups of women identified as Estrogen Dominant or Estrogen Deficient. Depending on whether
the women were Estrogen Dominant or Estrogen Deficient, they responded well to natural progesterone or estrogen, respectively. Even when natural estrogen was given, it was never without natural progesterone…A protocol was established after first levels were observed: 100 mg. of pure (natural) progesterone cream applied transdermally, (through the skin) bid. This amount was increased if the feeling of intense irritability persisted. From the beginning the serum levels responded to the progesterone increase by general elevation in progesterone, and a dramatic, over time
decrease in elevated estrogen.

Group 1,

Specifically, one month later the estradiol, which is the most commonly used form of estrogen for measuring overall serum values, was down to 400.3 pg/ml and the progesterone had climbed to 11.5 ng/ml. This trend continued for a year. [Note: Quest Lab Estradiol Luteal phase normal range: 48-440 pg/ml] … Subject one continued to experience increased feelings of well-being. The objective measurements correlated strongly with the interpretive aspects: there
were continued and generally improved feelings of calmness and factors related to the neuroinhibitory receptors in the brain, the part of the mid- brain which regulates anxiety. This is where progesterone does its neuro-chemical work. Estrogen works primarily on the serotonin pathways that affect
depression, not anxiety as much as the benzodiazapine receptors do.

Subject 2 was extremely interesting: Her feelings of increased well being correlated with the use of natural progesterone over time, however there is an important distinction between her symptoms and
those of subject 1. When her estrogen was high, and her progesterone levels were low,
she would exhibit extreme rage, followed by conciliatory, self-defeating demeanor the
next day. As time went by and her progesterone levels came up, she no longer became
as depressive following periods of anger and rage, which is how she manifested anxiety….Interestingly for subject 2, all her adult life she had thought she was prone to significant depression. She had been treated with psychotropic medications, specifically Paxil and Prozac with little relief. After treatment
with natural progesterone for fifteen months, from October of 1996 until December of 1997, she finally felt really well premenstrually for the first times in years. This has continued but with some variations…She reported feeling best at times when progesterone levels came up at least to 4 ng/ml, and estrogen levels decreased below 100 pg/ml…After the introduction of micronized progesterone, in the form of transdermal progesterone cream, pre-menstrual tension has essentially been obliterated….we are seeing this trend show up in many more subjects not in the original study but being seen at our clinic.

Group 2, Estrogen Dominance

The first woman, D, came in because of severe PMS. This refers to Pre-Menstrual
Syndrome that can involve headaches, bloating, significant mood changes, tension
and sometimes rage. Her gynecologist had treated her with various drugs, including
one to suppress testosterone; strangely, progesterone was not on the list. Her initial
serum progesterone at mid-cycle showed negligible progesterone at 1.4 ng/
ml, not nearly enough to mediate the high levels of estrogen. Her marriage was failing
because she was so irritable and she could not control it. She was one of those
miracle cases; we have several of these now. She said the first two week trial of using
progesterone was dramatic–she felt like herself for the first time in years. Initially
we gave her 1.6% over the counter progesterone. As her menstruation date approached
some symptoms intensified, notably irritability, and so we then ordered 6% progesterone from Women’s International Pharmacy, compounded to our specifications.
She has continued to thrive. I am continuing to follow her progress.

M is another anxious and irritable woman …Adding 10% natural micronized progesterone two weeks before her next menstrual cycle began has helped her distressed mood during that time even more. Although she has been a difficult woman to work with, she is showing improvement. She had initial mid-cycle progesterone levels of 0.4 ng/ml with an increase to 5.2 ng/ ml over four months.

The third woman, B, in this phase of the study demonstrated the classic symptoms of the estrogen dominant female more than any other I have seen. She had negligible (not measurable) luteal progesterone of less than 0.4 ng/ml, which is essentially off the scale. She came to our of fice hysterical saying she could not calm down and was having recurrent panic attacks
daily. She reported obsessive thought processes that were traumatic for her. She
was extremely high strung and felt she has ”no containment” for these virulent emotional
swings that upset her a great deal. She felt out of control with panic, rage, and
anger, mostly directed toward her husband.

Subject four, Q, was the extreme of a group of three women, with cases five and
six showing similar symptoms, but not as severe. So, in telling about Q, I see these
other two cases mirrored but their behavior was not as extreme. Q would
show no impulse control when angry and has wounded people irrevocably, or so it
would seem. Q was given high doses of the neuro-inhibitors GABA and Taurine at
750 mg. and 1000 mg. for three months. This helped her enormously in reducing
her feelings of panic. Cases five and six were given similar nutrients but in smaller
doses. During the luteal phase, particularly the week prior to menstruation, the
rage use to intensify. She has experienced steady improvement since she started using
100 mg. of natural progesterone six times a day. This is the dose that keeps
her sane. Over time, if she is able, this might be reduced. In the meantime there
is absolutely no harm in this protocol and it may help save her marriage. The other
two subjects in this subgroup responded to 300 mg. and 400 mg. during this time
period. Again, they were quite similar but less severe cases.

Summary of Clinical Studies

The clinical study found that a deficiency of progesterone is clearly implicated as a primary factor in
mid-life anxiety patterns. As women increased the uptake of natural progesterone at 100 mg/dose, serum progesterone levels increased and seemed to mediate excess estrogen. These changes in serum levels clearly correlated with the qualitative input given by these women on questionnaires
and in personal interviews.

Is mid-life anxiety in women connected to low progesterone levels or estrogen dominance? Mid-life anxiety in women correlated with anxiety being more extreme during the luteal phase, or latter two weeks of the menstrual cycle. Even though objectively this is when there is a gradual natural increase in progesterone production. The data showed that there is often too much estrogen to be mediated by
the body’s available progesterone.

women predisposed to anxiety patterns reported significant improvement in their well being while taking neuro-inhibitory amino acids alone (GABA, Taurine, Glutamine). However, as the ovulatory
peak of estrogen dominance started, and moved into the luteal phase, these effects
diminished, even in women using physiologic, low doses of progesterone. When neuro-inhibitory
amino acids were used in conjunction with pharmaceutical grade, natural progesterone, women thrived and reported greatly increased calmness, even during the normally difficult pre-menstrual phase.

Discussion:

The women with anxiety were treated with neuro-inhibitory nutrients, specifically amino acids such as GABA or Taurine. While there was initial improvement on amino acid therapy alone, the improvement
diminished in the premenstrual two-week period of time. We therefore conjecture that the calming effect of progesterone might be because it augments the effect of GABA, and acts like a benzodiazapine itself.

Over the initial six months the results were consistent and extraordinary. The data suggest that the incidence of anxiety decreased markedly when women were using trans-dermal natural progesterone
cream that largely bypasses liver function. Affirmative answers to question 1: “Are you anxious?” decreased over time congruent with the use of natural progesterone.

The evidence points toward the premise that in anxiety prone women, when progesterone levels are low relative to estrogen, these subjects feel tense and irritable, and exhibit other criteria of general anxiety. Relief of these symptoms is generally seen when progesterone is measured at 8-15 ng/
ml. The mood changes were qualified as follows. As the progesterone levels rose gradually, most symptoms of acute anxiety disappeared. Chronic symptoms took longer to dissipate, although they too diminished over time. The subjects also reported that if they were not diligent about using progesterone, symptoms recurred. As each woman was viewed individually, required progesterone
levels varied, based upon their biochemical individuality. These fluctuations are reflected in the data

I refer here to the recent work of John Lee. He is the pioneer in the use of natural progesterone. Lately, while I have always maintained that he is myopic I have found him misguided. In his zealousness to promote the use of his “physiologic” dose of progesterone I see women getting led astray. He insists that women need only small amounts of progesterone to get relief
for their peri-menopausal symptoms. This study strongly contradicts Dr. Lee’s approach. The women seen repeatedly reported that the changes in mood happened congruent with elevated serum hormone levels of progesterone, usually accompanied by a drop in high estrogen levels!
Early in our research these changes did not occur at physiologic doses (as promoted
by Dr. Lee) or when low dose progesterone was used at 1.6%.

I conjecture that the petrochemical estrogens in the environment, as well as E1 and E2 found in animal foods, elevate our own estrogenic response significantly.

Further, in women of peri-menopausal age there are substantial data linking women who are
estrogen dominant, i.e. top heavy in estrogen relative to progesterone, and irritability patterns and/or rage. Women tend to get more irritable and men tend more toward intense anger. There now appears
to be a biological basis to this, as well as a neuro-chemical one. There are data to support
the premise that estrogen itself is neuro-excitatory. High levels of estrogen may predispose certain women to high levels of anxiety, including panic attacks.

Natural progesterone has neuro-inhibitory or calming effects similar to GABA, taurine and other neuro-inhibiting or calming amino acid precursors to brain chemicals. The neurotransmitters are the chemical
languages that one part of the brain speaks to another domain. People who have trouble focusing, concentrating, or remembering how to do something are deficient in these biochemical messengers

================================================
Progesterone for PMS
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12) Once a Month: Understanding and Treating PMS Paperback – March 23, 1999 Katharina Dalton (Author)

Katharina Dalton- minimal dose vag supp 400 mg BID

13) Interview: Katharina Dalton, MD: Progesterone and Related Topics, Int Jounnal of Pharmaceutical Compounding 1999

I think the minimum dose, if you’re going to use vaginal suppositories, is 400 mg twice a day. First of all, you want a high dose. But the second thing we know about the unique characteristics of the progesterone receptor is that the first initial dose of progesterone, when you give it in rats, is effective; subsequently, they need a dose 40 times higher than the first dose to maintain the effect. What we tend to do there to overcome that is to use a high dose initially.

1953 BMJ Katharina Dalton

14) Greene, Raymond, and Katharina Dalton. “The premenstrual syndrome.” British medical journal 1.4818 (1953): 1007.

PMS symptoms: emotional instability, headache, backache, depression, abd bloating, fluid retention, weight gain, breast pain,

84 cases of PMS treated with ethisterone (progestin) and/or progesterone,

The visual symptoms noted in these 10 cases of migraine were: photophobia, 4; mistiness,1; hemianopia, 2; burning pain, 2; flashes of light,…In this series 70 patients expected attacks in the premenstrual week, 9 at the onset of menstruation, and 4 during menstruation.

The series is conspicuous for the normality of the menstrual history.

Is Water Retention the Cause of the Syndrome ? That the symptoms are due to water retention is strongly suggested by the oliguria and gain in weight which announces their arrival and the diuresis and loss of weight which accompanies their relief at, or soon after, the onset of menstruation.

the trouble was not so much a high level of oestradiol as a lack of antagonism by progesterone…the cause of the syndrome is an abnormally high oestradiol/progesterone ratio…painful breasts, so common a feature of the syndrome, are due to a high oestrogenic level,

the administration of progesterone is effective in relieving it…Migraine and lesser degrees of headache may well be due to an increased hydration within the indistensible cranium. The rhinorrhoea of the premenstrual syndrome-and perhaps the asthma as well-is thus explicable by the excessive
local activity of oestradiol

Treatment
Dehydration
Androgens
Vitamins
Progesterone

1) ethisterone, given in oral doses of 30 to 150 mg. daily for twelve days from the fourteenth day of the cycle

2) intramuscular injections of progesterone instead, in doses at first of 10 mg. daily during the
second half of the cycle. Later it was found that an injection of 25 mg. on alternate days was equally effective. Severe cases were treated by this method from the outset.

The oral administration of ethisterone gave complete relief in 22 cases (47.9%) and partial relief in a further 8 cases (17.4%).

The results with intramuscular progesterone in 61 cases were more satisfactory- (83.5%) became free from symptoms, 4 (6.6%) improved, and 4 (6.6%) obtained no relief.

A large proportion of women, estimated by one author as 40%, suffer a variety of distressing symptoms during the final week or so of the menstrual cycle. In occasional cases, similar symptoms may occur at monthly intervals at other points of the cycle. They are probably produced by water-retention, and the evidence at present suggests that this in its turn is due to abnormal elevation of the oestradiol/ progesterone ratio. Various treatments aimed at either dehydration or a correction of the disturbed hormonal ratio have proved partially effective. Treatment with a progestogen is almost invariably successful. In mild cases relief is usually obtained by the oral administration of ethisterone
in a dosage of 25 mg. twice daily during the second half of the menstrual cycle. A larger proportion of patients can be relieved by the intramuscular injection of progesterone, 25 mg. on alternate days during the same phase of the cycle. Such cases are more effectively treated, with less labour for the patient, by the implantation of progesterone, which remains effective for many months.

=======================

Katharina Dalton NY Times

15) The Prophet of PMS: By Lauren Slater Dec. 26, 2004 New York Times.

Dalton and Greene coined the term PMS in a pivotal paper they wrote in 1953. And it was Dalton’s tireless efforts that put PMS on the map. She wrote up case studies of women brought back from the brink by progesterone therapy. She did large-scale studies that showed schoolgirls’ grades declined by 10 percent premenstrually, followed by a 20 percent increase postmenstrually. She found that half of all female suicides in England in the 50’s and 60’s occurred in the four days before menstruation, as did half of crimes committed by women…GP who coined the term ‘premenstrual syndrome’ in 1953, then set up the first clinic to treat PMS and ran it for 40 years.

16) Zietal, Bianca, “Katharina Dorothea Dalton (1916–2004)”. Embryo Project Encyclopedia (2017-05-24). Arizona State University. School of Life Sciences. Center for Biology and Society. Embryo Project Encyclopedia.
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Treating PMS with Natural Progesterone

17) Dr. Phil Interview with Holly Anderson: Treating PMS Symptoms With Natural Progesterone .

The treatment that works is vaginal or rectal natural progesterone. [Progesterone cream works just as well or better because it’s not messy and drippy! It is delivered to cells throughout the body within minutes of application.] Oral [pill] progesterone does not work for PMS. […because it stresses the liver and creates a lot of metabolites or byproducts, and also only delivers about 20 percent of the dose to the cells].

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focused natural neurotransmitter support

18) Advanced Premenstrual Syndrome (PMS) and Premenstrual Dysphoric Disorder (PMDD)
Treatment by Marcelle Pick, OB/GYN NP Reviewed by Dr. Sarika Arora, MD

Natural neurotransmitter testing and support

For those women who are still symptomatic after boosting their nutritional support, making dietary changes, improving exercise habits, and using bioidentical progesterone support, we often consider more focused natural neurotransmitter support. Some options for targeting neurotransmitter function include the following:

omega–3 fatty acids in the form of EPA/DHA, boosting to 2–3 grams per day total.
5–HTP, 50–100 mg, generally taken in the evening. More may be needed during the PMS time-frame (up to 800 mg), but dosage and timing depend on your body’s individual make-up.
Vitamin D (25-OH vitamin D) blood testing and supplemental treatment to achieve optimal blood levels (50–60 ng/mL).

A trial of St. John’s wort, dosage and formulation varying with the individual, and not to be taken in conjunction with prescription antidepressants.

Where the conventional approach falls short —prescription antidepressants for PMS and PMDD

=================================================================

Supportive Study Progesterone for pms
300 MG PO MICRONIZED PROGESTERONE

19) Dennerstein, L., et al. “Progesterone and the premenstrual syndrome: a double blind crossover trial.” Br Med J (Clin Res Ed) 290.6482 (1985): 1617-1621.

Women were instructed to take one 100 mg capsule [PO micronized progesterone] in the morning and two 100 mg capsules at night as there had been reports of drowsiness of short duration. Treatment was prescribed for 10 days of each menstrual cycle starting roughly three days after ovulation. In each cycle ovulation was confirmed by determinations of urinary 24 hour pregnanediol and total oestrogen concentrations.

Our findings confirm descriptive reports of beneficial effects of progesterone on the symptoms of premenstrual tension. Improvements were attained both in mood symptoms such as anxiety, depression, and stress and in the physical complaints of swelling and hot flushes. Although not all variables reached a significant level of improvement, the direction of change for premenstrual complaints, with the exception of arousal, was always in favour of progesterone treatment.

Taken together the analyses also show the general positive effects of treatment. There was a trend to general improvement in almost all the physical and psychological variables over the four months of treatment, an improvement even more appreciable for the months of progesterone treatment alone.

This study showed that an oral formulation of micronised progesterone was effective in alleviating many premenstrual complaints including those of anxiety, stress, depression, hot flushes, swelling, and water retention.

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Chaste Tree: Vitex Agnus Castus for PMS

20) Davies, Sasha, and Tori Hudson. The Menopause Companion: A Beginner’s Guide to Owning Your Transition, from Peri to Post. Shambhala Publications, 2023.

21) Hudson, Tori. “Premenstrual syndrome–a review of herbal and nutritional interventions.” Townsend Letter for Doctors and Patients 270 (2006): 126-132.

22) Premenstrual Syndrome; A Natural Approach by Tori Hudson, N.D. Chaste Tree (Vitex agnus castus) by Tori Hudson

The single most important plant for the treatment of prementsrual syndrome is chaste tree berry. The effect of chaste tree is on the hypothalamus-hypophysis axis. It increases secretion of luteinizing hormone and also has an effect which favors progesterone.

Two surveys were done covering 1,542 women with PMS who had been treated with a German liquid extract of chaste tree for periods of up to 16 years. The average dose was 42 drops daily. Effectiveness as recorded by the patients’ doctors was either very good, good, or satisfactory in 92 percent of the cases. Use 35 drops of liquid tincture daily or a standardized extract containing .75% acubin at 175 mg per day or .6% aucubin at 215 mg per day.

The newest study using chaste tree was a clinical trial of 170 women with PMS; this has been the most well designed trial yet studying the efficacy of chaste tree in women’s health. Women were assigned to take either a tablet containing an extract of chaste tree berry (20 mg) or a placebo tablet once daily for three months. Subjective reporting of irritability, mood changes, anger, headache, breast tenderness and bloating were recorded. At the end of the three months, women taking the chaste tree reported a 52% reduction in PMS symptoms versus 24% reduction for those in the placebo group. Women in the chaste tree group reported their significant reduction in all symptoms except for bloating before the menses.

A study by Dennerstein and colleagues in 1985 found an overall beneficial effect using 300 mg/day (100 mg a.m., 200 mg p.m.) for 10 days of each menstrual cycle starting 3 days after ovulation. After only one month of treatment, those receiving progesterone could be clearly distinguished from those receiving placebo in areas of stress, anxiety, and concentration. Most all other symptoms also continued to improve with each menstrual cycle.

Natural progesterone creams have not been subjected to scientific scrutiny although tens of thousands of women can attest to their benefit. In my practice, I largely use the transdermal creams that contain at least 400 mg of natural progesterone per ounce. Using Â¼ tsp per dose, that will deliver approximately 20 mg of USP natural progesterone, the same progesterone that is in oral micronized progesterone. I recommend applying Â¼ tsp twice daily starting at mid-cycle and stopping the day before the menses is due. For women whose significant symptoms begin at ovulation, I recommend Â¼ tsp per day from day 8 to day 14 and then Â¼ tsp twice daily until just before the menses begins, as described above. The best sites for rubbing in the cream include the palms, inner upper arms, chest, and inner thighs.

================= BEST Pathogenesis of PMS 2023===================

23) Gao, Q., et al. “Role of allopregnanolone-mediated γ-aminobutyric acid A receptor sensitivity in the pathogenesis of premenstrual dysphoric disorder: Toward precise targets for translational medicine and drug development.” Frontiers in Psychiatry 14 (2023).

ZZZZZZZZZZZZZZZZ SSRI and OCP ZZZZZZZZZZZZZZZZZZZZZZZZZZZZ

24) Tiranini, Lara, and Rossella E. Nappi. “Recent advances in understanding/management of premenstrual dysphoric disorder/premenstrual syndrome.” Faculty reviews 11 (2022).

The spectrum of symptoms is wide and the most common are breast tenderness, bloating, headache, mood swings, depression, anxiety, anger, and irritability.

Thus, new therapeutic approaches to PMS/PMDD include inhibition of progesterone receptors in the brain (i.e., with ulipristal acetate), reduced conversion of progesterone to its metabolite allopregnanolone with dutasteride, and possible modulation of the action of allopregnanolone on the brain GABAergic system with sepranolone.

The most severe form of PMS is defined as premenstrual dysphoric disorder (PMDD), characterized predominantly by emotional and affective symptoms not due to another psychiatric condition4. PMDD was included as a new diagnostic category of depressive disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)5,6 and recently (2019) coded as a gynecological diagnosis in the World Health Organization’s International Classification of Diseases (ICD-11)7. A PMDD diagnosis requires the presence of at least one mood symptom (marked affective lability, irritability, depressed mood, anxiety, or tension) in a group of at least five (including loss of interest, subjective difficulty in concentrating, fatigue, marked appetite change with overeating or food cravings, insomnia or hypersomnia, feeling emotionally overwhelmed, and physical symptoms). Such symptoms should occur during the luteal phase of the majority of menstrual cycles over the previous year. Furthermore, they must be associated with clinically significant distress regarding social, academic, or working activities; they should not be the exacerbation of a chronic condition or the effect of medications, and they need to be confirmed by prospective daily ratings during at least two symptomatic cycles6.

According to a recent meta-analysis, premenstrual symptoms are very common, affecting about half of women of reproductive age worldwide8.

PMS is estimated to affect 20 to 30% of women in the United States2,

First-line treatments – SSRI

Currently, the first-line treatment for PMDD consists of selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, paroxetine, sertraline, and escitalopram21. Serotonin is a pivotal neurotransmitter modulating mood and behavior. It plays a fundamental role in the pathophysiology of PMS/PMDD because women with the condition have atypical serotonergic transmission, a lower density of serotonin transporter receptors, decreased plasmatic serotonin levels in the luteal phase, and higher serotonin responsiveness in the follicular rather than in the luteal phase 22.

Combined hormonal contraception (CHC) may represent an alternative to treatment. The rationale for CHC is the blockade of an ovulatory surge of sex steroids since premenstrual symptoms are not observed during anovulatory cycles29 and disappear when women undergo treatment with agonists of gonadotropin-releasing hormone (GnRH)30 or bilateral oophorectomy31. The most effective CHC is a combination of the progestogen drospirenone and ethinyl estradiol in a regimen with a shorter hormone-free interval (4 rather than 7 days)32,33

Converging evidence suggests that fluctuations of ovarian sex steroids (in particular, progesterone) are key factors for PMS/PMDD35, given the synchrony with the post-ovulatory phase and the reinstatement of symptoms during GnRH agonist treatment when add-back progesterone is administered36. Since women with PMDD have progesterone serum concentrations similar to those of healthy women37, the underlying mechanism of PMDD is presumed to be an increased sensitivity to fluctuations of this steroid38,39. Progesterone interacts with the chemistry of the central nervous system (CNS)40–42 by easily passing through the blood-brain barrier. Progesterone receptors (PRs) are indeed widespread in the amygdala, hippocampus, hypothalamus, and frontal cortex43,44.

Extensive research demonstrates that the central effects of progesterone on mood result largely from its metabolite allopregnanolone, a neuroactive steroid that acts as a strong positive modulator of the gamma-aminobutyric acid (GABA) receptor51–53. GABA is the main inhibitory neurotransmitter within the CNS and is a pivotal regulator of stress, anxiety, vigilance, and seizures37. The involvement of the GABAergic system in the pathophysiology of PMS/PMDD has recently aroused growing interest in finding new therapies directly focused on premenstrual symptoms. At high concentrations, allopregnanolone can cause sedation by activating the GABA receptor, but it may also induce paradoxical reactions with adverse moods in susceptible women54. Those with severe PMS/PMDD have normal levels of plasma allopregnanolone41,55–57, but some evidence showed diminished concentrations of allopregnanolone and its precursor progesterone and a blunted response to the GnRH test during the luteal phase of the menstrual cycle58. Fluctuations of allopregnanolone induce changes in the conformation of the GABA-A receptor sufficient to determine anxiety-like behaviors in predisposed women59,60. In light of these findings, the development of new treatments for PMDD attempted to stabilize allopregnanolone signaling50. Dutasteride, an inhibitor of the enzyme 5alpha-reductase that converts progesterone to allopregnanolone, was recently tested with the aim of modulating progesterone/allopregnanolone balance in women with PMDD. Dutasteride prevented the luteal phase increase in allopregnanolone and improved most PMDD symptoms (i.e., irritability, anxiety, sadness, food cravings, and bloating) without exerting any effect on healthy controls61. At present, dutasteride is a potential off-label option for women experiencing side effects or lacking benefits of SSRIs61.

The US Food and Drug Administration recently approved allopregnanolone itself (brexanolone) for the treatment of postpartum depression (PPD)68,69, a disorder extensively associated with PMS/PMDD70,71 in the context of reproductive depression72. Exposure to high allopregnanolone levels during pregnancy has a protective and mood-stabilizing effect, while in susceptible women, the sudden decrease in allopregnanolone following placental detachment at birth alters the GABAergic signaling73–76.

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PMS Syndrome- RCTS do not support use

25) Wyatt, Katrina, et al. “Efficacy of progesterone and progestogens in management of premenstrual syndrome: systematic review.” Bmj 323.7316 (2001): 776.

26) O’Brien, P. M. “Helping women with premenstrual syndrome.” BMJ: British Medical Journal 307.6917 (1993): 1471.

Progesterone and progestogens…The widespread use of progesterone probably results from the enthusiasm of its advocacy rather than its pharmacotherapeutic efficacy. Extensive anecdotal evidence has led to claims for efficacy by a few authors but randomised double blind placebo controlled trials
do not support this view.’7

Progesterone NO MORE EFFECTIVE THAN PLACEBO

27) Van Der Meer Y, Benedek-Jaszmann L, Van Loenen A. Effect of high-dose progesterone on the pre-menstrual syndrome; a double-blind cross-over trial. J Psychosomatic Obstet Gynaecol. 1983;2:220.

Abstract A double-blind cross-over placebo controlled trial was carried out to compare progesterone 200 mg with a placebo, both given in rectal suppositories, in 20 patients with the pre-menstrual syndrome (PMS). Each kind of suppository was used twice daily from mid-cycle to the onset of menstruation during two successive cycles. Six patients did not complete the trial. Daily scores for a number of psychological and somatic symptoms were recorded by the participants. Mean symptom scores in the last seven days of the pre-menstruum did not differ significantly between the two treatment periods. The participants did not express a significant preference for the progesterone therapy. Mean blood levels of FSH, oestradiol, prolactin and LH, determined on the first day of menstruation did not differ between the two periods of treatment. Side effects, in the form of electrolyte abnormalities or hepatic or renal function disturbances, were not seen. In this trial, progesterone 200 mg twice daily by the rectal route was not more effective than the placebo.

Progesterone NO MORE EFFECTIVE THAN PLACEBO

28) Sampson, G. A. “Premenstrual syndrome: a double-blind controlled trial of progesterone and placebo.” The British journal of psychiatry: the journal of mental science 135 (1979): 209-215.

Patients with premenstrual syndrome recorded their symptoms daily using menstrual distress questionnaires. These were analysed by a least mean square method of fitting sine waves. After recording an untreated cycle, patients were given progesterone 200 mg b.d. and placebo in a double-blind crossover manner; 75 per cent of patients were then given progesterone 400 mg b.d. and placebo in a similar manner. Treated cycles were rated by both daily menstrual distress questionnaires and retrospective self-assessment. Both rating methods showed there was no significant difference between progesterone and placebo in reducing symptoms of premenstrual syndrome, and in the majority of cases placebo was more effective, although never significantly so.

29) Maddocks, S., et al. “A double-blind placebo-controlled trial of progesterone vaginal suppositories in the treatment of premenstrual syndrome.” American Journal of Obstetrics and Gynecology 154.3 (1986): 573-581.
Rigorous criteria were used to select women with severe premenstrual syndrome for inclusion in an 8-month double-blind placebo-controlled clinical trial of progesterone vaginal suppositories. Following a control month without treatment, progesterone (200 mg in polyethylene glycol base) or placebo was self administered twice daily by vaginal suppository for a minimum of 12 days before the onset of menstruation for 3 months. Crossover to the opposite medication for a further 3 months was followed by a final control cycle without treatment in month 8. Physician contact was minimized throughout the study to avoid any possible positive effects of psychological support which may have confounded past investigations. Detailed self-report questionnaires were completed every 3 days for the duration of the study. Although the attrition rate was high, 20 women completed the trial and their records are analyzed here. The results of this trial indicate that the response to vaginal progesterone in these dosages is, at best, marginal and not significantly different from response with placebo use.

30) Freeman, E., et al. “Ineffectiveness of progesterone suppository treatment for premenstrual syndrome.” JAMA 264.3 (1990): 349-353.

Progesterone is the most widely used treatment for premenstrual syndrome. To answer definitely the question of whether progesterone suppositories are effective for the treatment of premenstrual syndrome, a randomized, placebo-controlled, double-blind crossover study of 168 women, receiving progesterone in doses of 400 and 800 mg or placebo, was carried out. Premenstrual symptoms were not significantly improved by progesterone compared with placebo in any measure used in the study, including daily symptom reports maintained throughout treatment, clinician evaluation of improvement, and patient global reports of symptoms severity, relief, and disruption of daily activity. No symptom cluster or individual symptom differed significantly between progesterone and placebo treatment. These treatment results were not significantly affected by fluctuations in response during the placebo washout period, pretreatment levels of depression or anxiety at either postmenstrual or premenstrual times, or any of 19 other background, medical history, or symptom variables examined individually as covariates with treatment.

CONVENTIONAL TREATMENT OF PMS – SSRI/OCP

American family physician 2016 PMS SSRI first Line Treatment

31) Hofmeister, Sabrina, and Seth Bodden. “Premenstrual syndrome and premenstrual dysphoric disorder.” American Family Physician 94.3 (2016): 236-240.

Premenstrual disorders affect up to 12% of women. The subspecialties of psychiatry and gynecology have developed overlapping but distinct diagnoses that qualify as a premenstrual disorder; these include premenstrual syndrome and premenstrual dysphoric disorder. These conditions encompass psychological and physical symptoms that cause significant impairment during the luteal phase of the menstrual cycle, but resolve shortly after menstruation. Patient-directed prospective recording of symptoms is helpful to establish the cyclical nature of symptoms that differentiate premenstrual syndrome and premenstrual dysphoric disorder from other psychiatric and physical disorders. Physicians should tailor therapy to achieve the greatest functional improvement possible for their patients. Select serotonergic antidepressants are first-line treatments. They can be used continuously or only during the luteal phase. Oral contraceptives and calcium supplements may also be used. There is insufficient evidence to recommend treatment with vitamin D, herbal remedies, or acupuncture, but there are data to suggest benefit from cognitive behavior therapy.

——————— –

32) Dickerson, Lori M., Pamela J. Mazyck, and Melissa H. Hunter. “Premenstrual syndrome.” American family physician 67.8 (2003): 1743-1752.

Historically, progesterone delivered by vaginal or rectal suppository has been widely prescribed for women with PMS. Synthetic progesterone-like drugs, such as medroxyprogesterone acetate (Provera), have also been studied. Paradoxically, some evidence indicates that progesterone may be responsible for some of the physical and emotional symptoms of PMS.1,35 The administration of progesterone is commonly associated with abdominal bloating and pain, nausea, breast discomfort, and menstrual irregularities.2 A systematic review36 of 14 randomized controlled trials found no improvement in overall symptoms among women taking progesterone.

Use of progesterone during the luteal phase remains one of the most controversial treatments for PMS. Because efficacy compared with placebo has not been demonstrated, progesterone is not recommended for the management of PMS.3

JAPAN 2023 OB/GyNEs PMS

33) Yoshimi, Kana, et al. “Current status and problems in the diagnosis and treatment of premenstrual syndrome and premenstrual dysphoric disorder from the perspective of obstetricians and gynecologists in Japan.” Journal of Obstetrics and Gynaecology Research 49.5 (2023): 1375-1382.

The most commonly used medication was oral contraceptive pills (OCPs) (98.1%), followed by the Kampo, traditional Japanese herbal medicines, Kamishoyosan (73.6%). Concern-
ing first-line drugs for treatment, OCPs were the most common (76.8%), followed by Kampo medicine (19.5%); selective serotonin reuptake inhibitors (SSRIs) were less frequently used (2.6%). Regarding first-line drugs among OCPs, 65.1% respondents reported drospirenone-ethinylestradriol use.

33) Takeda, Takashi. “Premenstrual disorders: Premenstrual syndrome and premenstrual dysphoric disorder.” Journal of Obstetrics and Gynaecology Research 49.2 (2023): 510-518.

Recently, the term premenstrual disorders (PMDs), which includes premenstrual syndrome and premenstrual dysphoric disorder as a continuum, has been proposed. Although the precise etiology of PMDs remains unknown, the involvement of hormonal fluctuations is clear. The brain transmitters, serotonin and γ-amino butyric acid, also seem to be involved. Serotonin reuptake inhibitors and oral contraceptives are the current mainstay of treatment, but these are insufficient. Even the currently used prospective two period symptom diary is not widely used in actual clinical practice, creating a major problem of discrepancy between research and clinical practice. In this review, I would like to outline the latest information and problems in the etiology, diagnosis, and treatment of PMDs, with an emphasis on promising new therapies.

Usually, five types of treatments are used: (1) nonpharmacologic, (2) antidepressants, (3) hormone therapy, (4) vitamin and complementary medicine, and (5) surgery.

Antidepressants
There is strong evidence for the use of SSRIs for the treatment of PMDD75 and they are considered a first line of treatment.4,33,76 Unlike the treatment of depression, the efficacy of SSRIs administered after the onset of symptoms has been reported in the case of PMDD, assuming a different mechanism of action.77

Hormone therapy Oral contraceptives
The purpose of hormonal treatment is to suppress ovulation., Oral contraceptives (OCPs) were the first drugs to be used. OCPs containing drospirenone and ethinyl estradiol significantly improved PMDD symptoms.78 Continuous dosing regimens are advantageous for improving premenstrual symptoms because they eliminate the hormone-free period compared with regimens with classical withdrawal periods.33 There are reports suggesting the effectiveness of sequential dosing.79,80

Vitamins and complementary medicine
A variety of alternative medicines are being used around the world, but the evidence is limited.33
Among them, vitamin B6 (pyridoxine) has been extensively studied and moderate benefit was reported in 100 mg of pyridoxine treatment for premenstrual symptoms.83 In the RCOG guidelines, vitamin B6 is listed as one of the first choices in the treatment algorithm.33
Calcium carbonate supplementation with 1200 mg daily was reported to be effective compared with placebo for premenstrual symptoms.84 However, this effect was only weak compared with that of fluoxetine.85

Vitex agnus castus (chasteberry) is widely used in Europe and has been the subject of numerous studies, with a meta-analysis of 17 trials reporting efficacy compared with placebo.86

In Japan, Kampo, a type of herbal medicine, has traditionally been used in general practice. In a survey of Japanese obstetricians and gynecologists, the frequency of use of Kampo medicine as a first-line treatment for PMDs was 19%, ranking second after OCPs. Kampo medicines are available as extracted powder manufactured as industrial products by pharmaceutical companies, and can be prescribed in the same way as Western medicines. Kampo medicines have a
high degree of uniformity of ingredients, and in the field of obstetrics and gynecology, their efficacy in the treatment of menopausal symptoms was examined using a placebo-controlled trial.87 The only efficacy studies for PMDD have been preliminarily conducted using one of the Kampo formula Kamisyoyosan.88

Kamisyoyosan has been reported to act on the brain serotonin system in a mouse model of depression,89 making it a promising therapeutic agent for PMDs.

Surgery
Surgical intervention, total hysterectomy and bilateral adnexectomy, is a permanent treatment limited to
cases of recurrence of intense symptoms.90
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PMS

34) Premenstrual Syndrome, Part 2, November 15, 2011 By OBGYN.net Staff

1. Hudson T. Premenstrual Syndrome. The Female Patient. 2002;27(5):47-49,59.

2. American College of Obstetrics and Gynecology (ACOG). Committee opinion. Int J Gynecol Obstet. 1995;50:80.

3. Dittmar F. Das pramenstruelle Spannungssyndrome. J Gynakol. 1989; 5(6):4-7.

4. Schellenberg R. Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomized, placebo controlled study. BMJ. 2001;20:134-137.

5. Turner S, Mills S. A double-blind clinical trial on a herbal remedy for premenstrual syndrome: a case study.Complement Ther Med. 1993;1:73-77.

6. Tamborini A, Taurelle R. “Value of standardized Ginkgo biloba extract in the management of congestive symptoms of premenstrual syndrome.” Gynecol Obstet. 1993;88: 447-457.

7. Stevinson C, Ernst E. A pilot study of Hypericum perforatum for the treatment of premenstrual syndrome. Br J Obstet Gynaecol. 2000;107:870-876.

8. Schildge E. Essay on the treatment of premenstrual and menopausal mood swings and depressive states. Rigelh Biol Umsch. 1964;19(2):18-22

9. Dalton K. The Premenstrual Syndrome and Progesterone Therapy. 2nd ed. Chicago, Ill: Year Book Medical Publishers; 1976.

10. Keye W Jr. Medical treatment of premenstrual syndrome. Can J Psychiatry. 1985;30:483-487.

11. moved to above area

12. moved to above area

13. moved to above area.

14. moved to above area.

15. Dennerstein L, Spencer-Gardner C, Gotts, G et al. Progesterone and the premenstrual syndrome: a double blind crossover trial. Br Med J. 1985;290:1617-1621.

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Jerilynn Prior MD

35) Prior, Jerilynn C. “Women’s reproductive system as balanced estradiol and progesterone actions—a revolutionary, paradigm-shifting concept in women’s health.” Drug Discovery Today: Disease Models 32 (2020): 31-40.

36) Gordon, Jennifer L., et al. “Efficacy of transdermal estradiol and micronized progesterone in the prevention of depressive symptoms in the menopause transition: a randomized clinical trial.” JAMA psychiatry 75.2 (2018): 149-157.

Transdermal estradiol (0.1 mg/d) or transdermal placebo for 12 months. Oral micronized progesterone (200 mg/d for 12 days) was also given every 3 months to women receiving active TE, and identical placebo pills were given to women receiving placebo.

Twelve months of TE+IMP were more effective than placebo in preventing the development of clinically significant depressive symptoms among initially euthymic perimenopausal and early postmenopausal women

?????????????? Progesterone for perimenopausal hot flashes and VMS ???????????????

37) Prior, Jerilynn C., et al. “Oral micronized progesterone for perimenopausal night sweats and hot flushes a Phase III Canada-wide randomized placebo-controlled 4 month trial.” Scientific Reports 13.1 (2023): 9082.

This study tested progesterone for perimenopausal hot flush ± night sweat (vasomotor symptom, VMS) treatment. It was a double-blind, randomized trial of 300 mg oral micronized progesterone@bedtime versus placebo for 3-months (m) after a 1-m untreated baseline during 2012/1–2017/4. We randomized untreated, non-depressed, screen- and baseline-eligible by VMS, perimenopausal women (with flow within 1-year), ages 35–58 (n = 189). Participants aged 50 (± SD = 4.6) were mostly White, educated, minimally overweight with 63% in late perimenopause; 93% participated remotely. The 1° outcome was 3rd-m VMS Score difference. Participants recorded VMS number and intensity (0–4 scale)/24 h on a VMS Calendar. Randomization required VMS (intensity 2–4/4) of sufficient frequency and/or ≥ 2/week night sweat awakenings. Baseline total VMS Score (SD) was 12.2 (11.3) without assignment difference. Third-m VMS Score did not differ by therapy (Rate Difference − 1.51). However, the 95% CI [− 3.97, 0.95] P = 0.222, did not exclude 3, a minimal clinically important difference. Women perceived progesterone caused decreased night sweats (P = 0.023) and improved sleep quality (P = 0.005); it decreased perimenopause-related life interference (P = 0.017) without increased depression. No serious adverse events occurred. Perimenopausal night sweats ± hot flushes are variable; this RCT was underpowered but could not exclude a minimal clinically important VMS benefit. Perceived night sweats and sleep quality significantly improved.

38) Prior, J. C. “Progesterone for treatment of symptomatic menopausal women.” Climacteric 21.4 (2018): 358-365.

39) Prior, J. C. “Progesterone for treatment of symptomatic menopausal women.” Climacteric 21.4 (2018): 358-365.

40) Prior, Jerilynn C. “Clearing confusion about perimenopause.” BC Med J 47.10 (2005): 538-42.

At present, no perimenopause therapies have been adequately validated in randomized controlled trials. However, based on the endocrine changes of perimenopause, cyclic or daily oral micronized progesterone in doses of 300 to 400 mg at bedtime appears to help with heavy flow, hot flushes, breast tenderness, and sleep (J.C.P., unpublished data, 2001).

41) Nolan, Brendan J., Bonnie Liang, and Ada S. Cheung. “Efficacy of micronized progesterone for sleep: a systematic review and meta-analysis of randomized controlled trial data.” The Journal of Clinical Endocrinology & Metabolism 106.4 (2021): e942-e951.

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Vitex for PMS
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Vitex used by Wild Chimpanzees

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42) Emery Thompson, Melissa, et al. “Hyperprogesteronemia in response to Vitex fischeri consumption in wild chimpanzees (Pan troglodytes schweinfurthii).” American Journal of Primatology: Official Journal of the American Society of Primatologists 70.11 (2008): 1064-1071.

Chimpanzees in Gombe National Park consume fruits of Vitex fischeri during a short annual fruiting season. This fruit species is a member of a genus widely studied for phytoestrogen composition and varied physiological effects. One particularly well-studied species, V. agnus-castus, is noted for its documented effects on female reproductive function, evidenced in increased progesterone levels and consequent regulation of luteal function. We examined reproductive hormone levels in both male and female chimpanzees during a 6-week period of intense V. fischeri consumption. V. fischeri consumption was associated with an abrupt and dramatic increase in urinary progesterone levels of female chimpanzees to levels far exceeding the normal range of variation. Female estrogen levels were not significantly impacted, nor were male testosterone levels. These are some of the first data indicating that phytochemicals in the natural diet of a primate can have significant impacts on the endocrine system, though the fluctuating nature of chimpanzee diet and reproductive function does not allow us
to determine whether the effects observed during this short period had a broader positive or negative impact on female fertility. Given the widespread use of various Vitex species by African primates and the as-yet-undescribed phytochemical properties of these species, we predict that our observations may be indicative of a broader phenomenon. Am. J. Primatol. 70:1064–1071, 2008.

43) Farhoodi, Moghadam, and S. M. A. Khalafi. “The effect Vitex Agnus-Castus on serum concentration of cortisol, progesterone and luteinizing hormone in dairy cows.” (2018): 2597-2606.

pdf
44) Haerifar, Naiyereh, et al. “The effect of vitex agnus castus extract on the blood level of prolactin, sex hormones levels, and the histological effects on the endometrial tissue in hyperprolactinemic women.” Crescent Journal of Medical & Biological Sciences 7.4 (2020).

Materials and Methods: To this end, of women at reproductive age with hyperprolactinemia who had referred to healthcare centers, 105 cases were selected and randomly assigned to three groups of bromocriptine, Dostinex, and Vitagnus. During the time of research (4 cycles), patients were treated with these drugs, and finally, the titer of prolactin, follicle-stimulating hormone (FSH), luteinizing hormone, and estrogen, and progesterone of the blood serum sample were measured accordingly. At the beginning of the follicular phase, the ultrasound scan was done to determine the endometrial thickness and if necessary, the histological study was conducted using the endometrial biopsy sample.
Results: Based on the results, the prolactin level in the bromocriptine group started to show a significant difference from previous cycles in the second cycle, and in the first cycle in the other two groups (P < 0.05). In addition, the rate of the decrease in endometrial thickness in the Vitagnus group was significant compared to other groups (P < 0.05). At the third stage and later, bromocriptine and Dostinex had a significant effect on the FSH level while the effect of Vitagnus was not significant at any of the stages. The results further revealed that the amounts of estradiol in the Vitagnus group had a significant increase compared to other groups (P < 0.05). The effect of Vitagnus and Dostinex tablets on the HL level appeared from the 4th and 3rd cycles onward, respectively, while no significant effect of bromocriptine was found at any of the stages. Eventually, the effect of the Vitagnus tablet on progesterone was remarkable compared to the other two mediations in the 2nd and 3rd cycles.
Conclusions: Similar to other drugs, Vitagnus has a significant effect on the amount of prolactin and sex hormones and thus can be successfully used in treating hyperprolactinemia. Finally, reductions in endometrial thickness were significant in the Vitagnus group compared to the other two groups.

pdf ************************* BEST ******************************

45) Wuttke, Wolfgang, et al. “Chaste tree (Vitex agnus-castus)–pharmacology and clinical indications.” Phytomedicine 10.4 (2003): 348-357.

Extracts of the fruits of chaste tree (Vitex agnus castus = AC) are widely used to treat premenstrual symptoms. Double-blind placebo-controlled studies indicate that one of the most common premenstrual symptoms, i.e. premenstrual mastodynia (mastalgia) is beneficially influenced by an AC extract. In addition, numerous less rigidly controlled studies indicate that AC extracts have also beneficial effects on other psychic and somatic symptoms of the PMS. Premenstrual mastodynia is most likely due to a latent hyperprolactinemia, i.e. patients release more than physiologic amounts of prolactin in response to stressful situations and during deep sleep phases which appear to stimulate the mammary gland. Premenstrually this unphysiological prolactin release is so high that the serum prolactin levels often approach heights which are misinterpreted as prolactinomas. Since AC extracts were shown to have beneficial effects on premenstrual mastodynia serum prolactin levels in such patients were also studied in one double-blind, placebo-controlled clinical study. Serum prolactin levels were indeed reduced in the patients treated with the extract. The search for the prolactin-suppressive principle(s) yielded a number of compounds with dopaminergic properties: they bound to recombinant DA2-receptor protein and suppressed prolactin release from cultivated lactotrophs as well as in animal experiments. The search for the chemical identity of the dopaminergic compounds resulted in isolation of a number of diterpenes of which some clerodadienols were most important for the prolactin-suppressive effects. They were almost identical in their prolactin-suppressive properties than dopamine itself. Hence, it is concluded that dopaminergic compounds present in Vitex agnus castus are clinically the important compounds which improve premenstrual mastodynia and possibly also other symptoms of the premenstrual syndrome

46) Zahid, Hina, Ghazala H. Rizwani, and Sumaira Ishaqe. “Phytopharmacological review on Vitex agnus-castus: a potential medicinal plant.” Chinese Herbal Medicines 8.1 (2016): 24-29.

47) Niroumand, Mina Cheraghi, Fatemeh Heydarpour, and Mohammad Hosein Farzaei. “Pharmacological and Therapeutic Effects of Vitex agnus‑castus L.: A Review.” Pharmacognosy Reviews 12.23 (2018).

Vitex Chasteberry is EFFECTIVE for PMS

48) Seidlova-Wuttke, Dana, and Wolfgang Wuttke. “The premenstrual syndrome, premenstrual mastodynia, fibrocystic mastopathy and infertility have often common roots: effects of extracts of chasteberry (Vitex agnus castus) as a solution.” Clinical Phytoscience 3 (2017): 1-11.

It is well accepted that prolactin release can be reduced by dopamine and dopaminergic drugs. The efficacy of VAC extracts to ameliorate prolactin induced premenstrual mastodynia was therefore suggestive that VAC may contain dopaminergic compounds. Indeed, a number of diterpenes were identified that bound to recombinant Dopamine receptors of the 2 subtype (D2 receptors) which are present in pituitary lactotropes and which mediate the inhibitory effects of dopamine and dopaminergic drugs on pituitary prolactin release. Consequently, prolactin release in vitro from dispersed pituitary cells and in vivo in rats and postmenopausal women was inhibited by VAC 1095. Placebo controlled studies proved also the efficacy of VAC extracts to ameliorate premenstrual symptoms. In several placebo-controlled studies a clear relation between reduction of breast pain and reduction of serum prolactin levels could be established. In addition VAC extracts was also highly effective in women suffering from fibrocystic mastopathy. In many of these women serum prolactin levels were also elevated and reduced by VAC extracts.

The results from all trials suggested that VAC extracts ameliorated premenstrual symptoms including mastodynia, premenstrual dysphoric disorder and latent hyperprolactinemia. Cystic mastopathy and sterility due to corpus luteum insufficiencies were also beneficially influenced.

Adverse events with VAC were mild and generally infrequent.

Vitex for Cystic Mastalgia

49) Carmichael, A. R. “Can Vitex agnus castus be used for the treatment of mastalgia? What is the current evidence?.” Evidence‐Based Complementary and Alternative Medicine 5.3 (2008): 247-250.

There have been many treatments suggested for the management of mastalgia; one of these is the fruit extract of Vitex Agnus castus L. commonly known as Agnus castus, a deciduous shrub native to Mediterranean Europe and Central Asia. The use of herbal treatments in the management of pain is well documented (2). Agnus castus, like other herbal treatments (3), has been used in the treatment of many conditions of women’s health such as menstrual disorders (amenorrhea, dysmenorrhea), premenstrual syndrome, corpus luteum insufficiency, hyperprolactinemia, infertility, acne, menopause and disrupted lactation (4–12). Agnus castus is thought to be affective in the management of mastalgia because of its dopminergic effects. It is postulated that A. castus suppresses the stress-induced latent hyperprolactinemia in patients suffering from cyclical mastalgia. The purpose of this review is to analyze the current evidence available for the efficacy and safety of A. castus in the management of mastalgia.

Agnus castus may have therapeutic role in the management of cyclical mastalgia by controlling hyper-secretion of prolactin. The ability to lower the prolactin level in women with cyclical mastalgia has been shown in clinical and laboratory studies (15–17). A prolactin-suppressive effect of A. castus is thought to be due to a number of diterpenes including clerodadienols (15). These compounds manifest their dopminergic properties by binding to recombinant DA2-receptor protein, which has been shown to suppress prolactin release from cultivated lactotrophs and also in-vivo in animal experiments. These substances are almost identical in their prolactin-suppressive properties as dopamine itself (15). Addition of A. castus significantly inhibits basal as well as TRH-stimulated prolactin secretion of rat pituitary cells in vitro, as demonstrated in the primary cell culture experiments (18). These experiments also found that adding a dopamine receptor blocker could prevent this A. castus-induced inhibition of prolactin secretion. Authors suggested that because of its dopaminergic effect A. castus could be considered as an efficient alternative phytotherapeutic drug in the treatment of hyperprolactinemia. Other studies have demonstrated that inhibition of prolactin secretion by A. castus is dependent on the initial level of prolactin and the dose of A. castus and is independent of gonadotrophins (19,20).

ADVERSE EVENTS OF VITEX

The most frequent adverse events associated with the use of A. castus are nausea, headache, gastrointestinal disturbances, menstrual disorders, acne, pruritus and erythematous rash. Data available from clinical trials, post-marketing surveillance studies, surveys, spontaneous reporting schemes, manufacturers and herbalist organizations have recently been reviewed (28). The adverse events following A. castus treatment are mild and reversible indicating that A. castus is a safe herbal medicine. (28). Data of The German Commission E has approved the use of A. castus for mastalgia. No drug interactions have been reported.

There is convincing laboratory-based and clinical evidence available that A. castus is safe, effective and efficient in the treatment of cyclical mastalgia. It has a safe side effect profile and can be used safely for the treatment of cyclical mastalgia.

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meta-analysis of 17 trials reporting efficacy of Vitex compared with placebo on total premenstrual syndrome symptoms
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50) Verkaik, Saskia, et al. “The treatment of premenstrual syndrome with preparations of Vitex agnus castus: a systematic review and meta-analysis.” American Journal of Obstetrics and Gynecology 217.2 (2017): 150-166.

Vitex agnus castus (chasteberry), widely usedin Europe: meta-analysis of 17 trials reporting efficacy compared with placebo.

Thirteen of 14 studies with placebo, dietary supplements, or herbal preparations as controls reported positive effects of Vitex agnus castus on total premenstrual syndrome symptoms.

51) Schellenberg, Ruediger. “Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomised, placebo controlled study.” Bmj 322.7279 (2001): 134-137.

Institute for Health Care and Science, 35625 Hüttenberg, Germany

Randomised, double blind, placebo controlled, parallel group comparison over three menstrual cycles.
Setting General medicine community clinics.
Participants 178 women were screened and 170 were evaluated (active 86; placebo 84). Mean age was 36 years, mean cycle length was 28 days, mean duration of menses was 4.5 days.
Interventions Agnus castus (dry extract tablets) one tablet daily or matching placebo, given for three consecutive cycles.
Main outcome measures Main efficacy variable: change from baseline to end point (end of third cycle) in women’s self assessment of irritability, mood alteration, anger, headache, breast fullness, and other menstrual symptoms including bloating. Secondary efficacy variables: changes in clinical global impression (severity of condition, global improvement, and risk or benefit) and responder rate (50% reduction in symptoms).
Results Improvement in the main variable was greater in the active group compared with placebo group (P<0.001). Analysis of the secondary variables showed significant (P<0.001) superiority of active treatment in each of the three global impression items. Responder rates were 52% and 24% for active and placebo, respectively. Seven women reported mild adverse events (four active; three placebo), none of which caused discontinuation of treatment.
Conclusions Dry extract of agnus castus fruit is an effective and well tolerated treatment for the relief of symptoms of the premenstrual syndrome.

52) Zamani, Mehrangiz, Nosrat Neghab, and Saadat Torabian. “Therapeutic Effect of Vitex Agnus Castus in Patients with Premenstrual Syndrome.” Acta Medica Iranica 50.2 (2012): 101-106.

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Anti-Cancer Activity of Vitex

53) Ibrahim, Faten M., et al. “Vitex agnus-castus L.(Chasteberry) extracts shows in vitro and in vivo anti-inflammatory and anti-tumor propensities via reduction of cyclooxygenase-2 activity and oxidative stress complications.” South African Journal of Botany 143 (2021): 363-373.
This study tend to show that vitex extract/fractions possess anti-inflammatory, antioxidant propensities and cyclooxygenase inhibitory properties which could justify the promising antitumor properties and be further studied in the development of biomedicine.

Vitex is well known as a natural botanical supplement used to manage a panoply of ailments.
•Extracts and ethyl acetate fractions significantly and selectively suppressed COX-2.•Extracts significantly reduced the viable Ehrlich cell count in vivo.
•The promising antitumor properties shall open new industrial application of vitex.

54) El-Newary, Samah A., Eman R. Youness, and Abeer Ibrahim. “Vitex Berries Attenuates Chemically-Induced Mammary Carcinomas in Rats through modulation of the cancer growth rate-limiting enzymes activities: aromatase and Na+/K+ ATPase.” Egyptian Journal of Chemistry 67.5 (2024): 235-255.

Vitex (Vitex agnus-castus) berries have shown potent antioxidant, selective anti-inflammatory against cyclo-oxygenase-2 (COX-2), and cytotoxicity effect against human breast cancer cells (MCF-7), as we recorded in our previous study”. Additionally, we found that Ethanolic extract (70%) and its ethyl acetate fraction have exhibited anti-tumor ability on Ehrlich’s Ascites Carcinoma in mice model in our previous study. The present study was planned to evaluate the protective and therapeutic effects of berries ethanolic extract and its ethyl acetate fraction on breast cancer using a 7, 12- dimethylbenz(a)anthracene-induced breast cancer model. Results showed that Vitex materials exhibited protective and therapeutic effects on chemically-induced breast cancer Sprague-Dawley female rats, where breast cancer biomarkers including the number of tumors devolved, weight and volume of tumor mass, and carcinoembryonic antigen level were significantly reduced compared to the cancer control group. Interestingly, the therapeutic effects of vitex materials were better
than the protective effects, and ethyl acetate fraction was more effective than ethanolic extract. Finally, the obtained data showed that Vitex ethanolic extract (70%) and its ethyl acetate fraction can protect and treat chemically-induced breast cancer with a good safety margin. Vitex struggled with chemically-induced breast cancer through inhibition of the overexpression of cancer growth rate-limiting enzymes; Na+/K+ ATPase and aromatase as well as estrogen overproduction. Also, Vitex prevented overexpression of COX-2 and oxidative stress.

55) El Kamari, Fatima, et al. “Anti-inflammatory and analgesic effects of aqueous extracts of Vitex agnus cactus L. and Cymbopogon nardus L. against carrageenan-induced inflammation in rats.” Trends in Phytochemical Research 1.1 (2024): 18.

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Myo-Inositol to Restore Regular Menstrual Cycles and Stop Abnormal Bleeding

56) Dikke, Galina B., et al. “Experience of treating patients with abnormal uterine bleeding associated with ovulatory dysfunction.” Obstetrics and Gynecology 3 (2024): 142-152.

Abnormal uterine bleeding (AUB) associated with ovulatory disfunction (OD) is the most common finding among women with chronic AUB, accounting for 57.7% of cases. Oral progestogens are often prescribed for irregular and copious menstruation. However, a course of hormonal rehabilitation after AUB-OD may not be enough. Inositols have been shown to be highly effective in restoring ovulation, normalizing the menstrual cycle, correcting carbohydrate and lipid metabolism, and reducing body weight.

Objective: To evaluate the effectiveness of complex treatment consisting of a combination of gestagen, iron medication and complex containing myoinositol, D-chiroinositol (5:1), folic acid and manganese in reproductive-aged patients with abnormal uterine bleeding associated with type I–III ovulatory dysfunction.

Materials and methods: The multicentre study in real clinical practice included 2,042 women with OD. The patients received dydrogesterone or micronized progesterone for 3 cycles (from 14 to 25 days), a medication containing myoinositol 1000 mg, D-chiroinositol 200 mg, folic acid 200 mg, manganese 5 mg (Dikirogen) for 6 cycles, iron sulfate/ascorbic acid for 3–4 months (according to indications). The parameters of the menstrual cycle (MC), hemoglobin, serum ferritin, and body weight were assessed at 3, 6 and 12 months from the start of treatment.

Results: The age of the patients ranged from 18 to 45 years, the average age was 30 (25; 35) years. The number of patients with a normal MC rhythm after 3 and 6 months was observed in 76.5 and 90.9% of patients versus 46.9% before treatment, p<0.001, and with a moderate volume of menstruation in 77.9 and 89.9% versus 45.4%, respectively, p<0.001; iron deficiency anaemia decreased from 39.9% to 18.2% of patients after 3 months, p<0.001, and there were no patients with anaemia by 6 months. Menstrual cyclicity remained at the achieved level, and the volume of blood loss decreased statistically significantly by 12 months. BMI decreased from 26.8 (21.3; 27.3) to 23.4 (21.3; 24.3) kg/m2 by 6 months of treatment, p=0.001, and stabilized at this level until 12 months.

Conclusion: Therapy for OD with progestin/Dikirogen in the first 3 months followed by administration of only Dikirogen for 3 months and symptomatic treatment with iron is effective in achieving regular menstrual cycle and volume of menstrual blood loss, eliminating anaemia and normalizing body weight.

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57) Carlini, Sara V., et al. “Management of premenstrual dysphoric disorder: a scoping review.” International Journal of Women’s Health (2022): 1783-1801.

Neuroactive metabolites of progesterone, which rise sharply in the late luteal phase, have been heavily implicated. Most evidence implicates the specific metabolite allopregnanolone: its interaction with GABA-A receptors in the brain has been hypothesized to provoke the affective symptoms of PMS and PMDD in a subset of women.23,24 In studies of women with PMDD, altered sensitivity to allopregnanolone has been found compared to controls.25 Despite these findings, the specific mechanism by which allopregnanolone contributes to negative mood symptoms in susceptible women remains elusive, partly due to the variability of responses observed.

A total of 113 articles were thus selected

Evidence from multiple randomized controlled trials (RCTs) has established that selective serotonin reuptake inhibitors (SSRIs), dosed continuously or only in the luteal phase of the menstrual cycle, are the gold standard of treatment for PMDD as per expert guidelines.29

The mechanism by which SSRIs treat PMDD is hypothesized to be distinct from the mechanism by which they are thought to treat other depressive and anxiety disorders, as the effect on symptoms is rapid and achieved at relatively low doses.30

One hypothesis is that SSRIs may modulate the synthesis of allopregnanolone,31 and one open-label trial of sertraline for PMDD demonstrated changes in total peripheral allopregnanolone levels, although these changes varied based on the subjects’ baseline levels.32

Sertraline,33,34 escitalopram,35–37 paroxetine,38–43 and fluoxetine44–46 dosed continuously or only in the luteal phase of the menstrual cycle have all been shown to be efficacious in the treatment of PMDD (Table 2). Luteal phase dosing of fluoxetine has also been shown to be efficacious as a dose of 90 mg given 14 days prior to menses and then again 7 days prior to menses.45 Sertraline47 dosed continuously, in the luteal phase, or at symptom-onset and fluoxetine48 dosed continuously have additionally been shown to be efficacious in the treatment of severe PMS

There are ample data that combined oral contraceptives (COCs) are effective treatment for somatic symptoms of the menstrual cycle, including but not limited to dysmenorrhea, gastrointestinal changes, and menorrhagia. However, data concerning the effect of COCs on affective premenstrual symptoms have been inconsistent.57 The data are further complicated by the availability of different combinations of hormones as well as different doses, usage, and timing.
Drospirenone, a progesterone derivative, combined with ethinyl estradiol (EE) is the only current United States Food and Drug Administration (FDA) approved COC for the treatment of PMDD.

A recent meta-analysis of COCs for PMDD or PMS concluded that while COCs were shown to be effective for symptom reduction overall, they were not effective for depressive symptoms specifically, and no specific formulation has shown superiority over the others to date.66

Progesterone

To date, progesterone-only interventions have not consistently demonstrated reduction of PMS and PMDD symptoms.67

One open-label study of 37 women given 100 mg of sublingual micronized progesterone on day 11 to day 25 of their cycles across three cycles reported significant efficacy of treatment over placebo, with authors hypothesizing that increased bioavailability of sublingual dosing may be responsible for the observed results.68

One RCT assessing progesterone receptor modulator ulipristal dosed as 5 mg daily over 28 days showed significant increase in remission of PMDD in the treatment arm, a promising result warranting further study.69

Estrogen
There is weak evidence concerning the efficacy of unopposed estrogen to suppress ovulation as a treatment PMS, and it may actually worsen symptoms in some women.70 Estrogen given as either a patch or implant to suppress ovulation

A 2016 meta-analysis of 12 heterogeneous case–control studies also demonstrates efficacy of pyridoxine over placebo for treatment of PMS.142

an upper-limit of 100 mg/day has been suggested for adults using pyridoxine.141

Such dysregulation of calcium homeostasis has been implicated in affective disorders.148 Oral calcium at doses of 500 mg daily149 and twice per day150 has been shown to improve symptoms of PMS in RCTs. Calcium in conjunction with pyridoxine and with thiamine144 has been demonstrated to be more efficacious than either of those vitamins alone.

A pilot study comparing calcium 600 mg twice daily compared to fluoxetine found a small effect of calcium and a larger effect of fluoxetine,151 in line with the overall small effect for calcium on total PMS symptoms compared to placebo (48% vs 30% reduction) observed in the largest RCT of calcium for PMS to date.15

A meta-analysis of studies on myo-inositol, a sugar-like molecule involved in stress response and the serotonin-signaling system, for depression and anxiety disorders that included two RCTs of PMDD, reported a trend toward efficacy on depressive symptoms over placebo.163

Mukai T, Kishi T, Matsuda Y, Iwata N. A meta-analysis of inositol for depression and anxiety disorders. Hum Psychopharmacol. 2014;29 (1):55–63. doi:10.1002/hup.2369

Surgery
Hysterectomy with Bilateral Salpingectomy/Oophorectomy (BSO)
Hysterectomy with BSO has been successfully utilized as a definitive treatment option for women with PMDD refractory to other interventions.201,202

A retrospective study of 47 women who underwent hysterectomy with BSO reported a 96% satisfaction rate and a 93.6% remission rate, with women reporting an average of nearly 10 years of distressing symptoms prior to the procedure.201

Seventeen women in the cohort additionally suffered from symptoms such as menorrhagia, uterine fibroids, and ovarian cysts, providing additional indications for surgery.201
As with all therapies resulting in ovulatory suppression, hormonal add-back is required following surgery to prevent the complications of medical menopause.201

More Vitex References = from Carlini =

58) Merz PG, Gorkow C, Schrödter A, et al. The effects of a special Agnus castus extract (BP1095E1) on prolactin secretion in healthy male subjects. Exp Clin Endocrinol Diabetes. 1996;104(6):447–453. doi:10.1055/s-0029-1211483121. Webster DE, He Y, Chen SN,

59) Pauli GF, Farnsworth NR, Wang ZJ. Opioidergic mechanisms underlying the actions of Vitex agnus-castus L. Biochem Pharmacol. 2011;81(1):170–177. doi:10.1016/j.bcp.2010.09.013122.

60) Ibrahim NA, Shalaby AS, Farag RS, Elbaroty GS, Nofal SM, Hassan EM. Gynecological efficacy and chemical investigation of Vitex agnus-castus L. fruits growing in Egypt. Nat Prod Res. 2008;22(6):537–546. doi:10.1080/14786410701592612123.

61) Momoeda M, Sasaki H, Tagashira E, Ogishima M, Takano Y, Ochiai K. Efficacy and safety of vitex agnus-castus extract for treatment of premenstrual syndrome in Japanese patients: a prospective, open-label study. Adv Ther. 2014;31(3):362–373. doi:10.1007/s12325-014-0106-z124.

62) Ambrosini A, Di Lorenzo C, Coppola G, Pierelli F. Use of Vitex agnus-castus in migrainous women with premenstrual syndrome: an open-label clinical observation. Acta Neurol Belg. 2013;113(1):25–29. doi:10.1007/s13760-012-0111-4125.

63) He Z, Chen R, Zhou Y, et al. Treatment for premenstrual syndrome with Vitex agnus castus: a prospective, randomized, multi-center placebo controlled study in China. Maturitas. 2009;63(1):99–103. doi:10.1016/j.maturitas.2009.01.006

64) Ma L, Lin S, Chen R, Wang X. Treatment of moderate to severe premenstrual syndrome with Vitex agnus castus (BNO 1095) in Chinese women. Gynecol Endocrinol. 2010;26(8):612–616. doi:10.3109/09513591003632126127.

65) Carlomagno, Gianfranco, et al. “Myo‐inositol in the treatment of premenstrual dysphoric disorder.” Human Psychopharmacology: Clinical and Experimental 26.7 (2011): 526-530.

66) Sharma, Neha, et al. “Myo-inositol: a potential prophylaxis against premature onset of labour and preterm birth.” Nutrition research reviews 36.1 (2023): 60-68.

5-HTP / Tryptophan

67) Menkes DB, Coates DC, Fawcett JP. Acute tryptophan depletion aggravates premenstrual syndrome. J Affect Disord. 1994;32:37–44.

pdf
68) Steinberg, Susanne, et al. “A placebo-controlled clinical trial of L-tryptophan in premenstrual dysphoria.” Biological psychiatry 45.3 (1999): 313-320.

In a randomized controlled clinical trial, 37 patients with premenstrual dysphoric disorder were treated with L-tryptophan 6 g per day, and 34 were given placebo. The treatments were administered under doubleblind conditions for 17 days, from the time of ovulation to the third day of menstruation, during three consecutive menstrual cycles.

Results: The Visual Analogue Scales (VAS) revealed a significant (p 5 .004) therapeutic effect of L-tryptophan relative to placebo for the cluster of mood symptoms comprising the items of dysphoria, mood swings, tension, and irritability. The magnitude of the reduction from baseline in maximum luteal phase VAS-mood scores was 34.5% with L-tryptophan compared to 10.4% with placebo.
Conclusions: These results suggest that increasing serotonin synthesis during the late luteal phase of the menstrual cycle has a beneficial effect in patients with premenstrual dysphoric disorder.

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Evening Primrose Oil

69) Budeiri, D., A. Li Wan Po, and J. C. Dornan. “Is evening primrose oil of value in the treatment of premenstrual syndrome?.” Controlled clinical trials 17.1 (1996): 60-68.

70) Khoo, Soo Keat, Claud Munro, and Diana Battistutta. “Evening primrose oil and treatment of premenstrual syndrome.” Medical journal of Australia 153.4 (1990): 189-192.

Black Cohosh

71) Hedaoo, Kritiksha, et al. “Exploring the Efficacy and Safety of Black Cohosh (Cimicifuga racemosa) in Menopausal Symptom Management.” Journal of Mid-life Health 15.1 (2024): 5-11.

72) Sadahiro, Ryoichi, et al. “Black cohosh extracts in women with menopausal symptoms: an updated pairwise meta-analysis.” Menopause 30.7 (2023): 766-773.

73) Hedaoo, Kritiksha, et al. “Exploring the Efficacy and Safety of Black Cohosh (Cimicifuga racemosa) in Menopausal Symptom Management.” Journal of Mid-life Health 15.1 (2024): 5-11.

74) Pavicic, Elena, et al. “The influence of Black Cohosh on hippocampal and hypothalamic gene expression profiles in ovariectomized rats and its potential to treat menopausal decrease in smell discrimination.” Archives of gynecology and obstetrics (2024): 1-9.

75) Dernbach, Matthew Robert, et al. “Black Cohosh Interactions with Prescription Medications Associated with Serotonin Toxicity and Rhabdomyolysis: A Case Report.” The Journal of Emergency Medicine 66.5 (2024): e592-e596.

Pregnenolone

76) Guennoun, Rachida. “Progesterone in the brain: hormone, neurosteroid and neuroprotectant.” International journal of molecular sciences 21.15 (2020): 5271.

Progesterone is also a neurosteroid as it can be synthesized locally in the nervous system by glia and neurons [1,2,9,18–21]. Progesterone synthesis requires the conversion of cholesterol to pregnenolone by the cytochrome P450scc enzyme and then the conversion of pregnenolone to progesterone by the 3-hydroxysteroid dehydrogenases (3-HSD).

77) Raux, Pierre‐Louis, et al. “New perspectives on the role of the neurosteroid pregnenolone as an endogenous regulator of type‐1 cannabinoid receptor (CB1R) activity and function.” Journal of Neuroendocrinology 34.2 (2022): e13034.

78) Lin, Yiqi Christina, et al. “The neurosteroid pregnenolone is synthesized by a mitochondrial P450 enzyme other than CYP11A1 in human glial cells.” Journal of Biological Chemistry 298.7 (2022).

79) Sripada, Rebecca K., et al. “Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits.” Biological psychiatry 73.11 (2013): 1045-1053.

80) Marx, Christine E., et al. “Olanzapine and fluoxetine administration and coadministration increase rat hippocampal pregnenolone, allopregnanolone and peripheral deoxycorticosterone: implications for therapeutic actions.” Pharmacology Biochemistry and Behavior 84.4 (2006): 609-617.

81) Heydari, Bobby, and Jean-Michel Le Mellédo. “Low pregnenolone sulphate plasma concentrations in patients with generalized social phobia.” Psychological medicine 32.5 (2002): 929-933.

Vitamin B6

Image showing Serotonin syhnthesis requires B6

82) Vleugels, Rut, Heleen Verlinden, and Jozef Vanden Broeck. “Serotonin, serotonin receptors and their actions in insects.” Neurotransmitter 2 (2015).

83) P5P is also a cofactor in the synthesis of dopa to dopamine in the pathway converting tyrosine to epinephrine and norepinephrine (Van Praag and Lemus, 1986).

85) Samieipoor S, Kiani F, Sayehmiri K, et al. Effects of vitamin B6 on premenstrual syndrome: a systematic review and meta-analysis. J Chem Pharm Sci. 2016;9(3):1346–1353

86) Samieipoor S, Kiani F, Sayehmiri K, et al. Effects of vitamin B6 on premenstrual syndrome: a systematic review and meta-analysis. J Chem Pharm Sci. 2016;9(3):1346–1353

As an immediate precursor of serotonin and dopamine, vitamin B6 can alleviate PMS
symptoms through its role in the production of prostaglandin and fatty acids. Moreover, vitamin B6 deficiency will reduce dopamine levels in kidneys.

Conclusion: The results of our meta-analysis confirmed vitamin B6 as a beneficial, inexpensive, and effective treatment for PMS symptoms. Therefore, the administration of this treatment option will enable midwives to achieve the important goal of reducing PMS symptoms

87) Retallick-Brown, Hāna, Neville Blampied, and Julia J. Rucklidge. “A pilot randomized treatment-controlled trial comparing vitamin B6 with broad-spectrum micronutrients for premenstrual syndrome.” The Journal of Alternative and Complementary Medicine 26.2 (2020): 88-97.

Premenstrual syndrome (PMS) affects 20%-30% of women but current medical treatments are limited in their efficacy. The objective of this study was to compare efficacy of a broad-spectrum micronutrient formula (consisting mainly of minerals and vitamins) to a single vitamin (B6) for treatment of PMS, for which B6 has already been shown to be efficacious. Methods: This double-blind, randomized, treatment-controlled trial allocated 78 (72 completed) regularly menstruating women with PMS to consume micronutrients or vitamin B6 (80 mg/day) daily following a two-cycle baseline period, for three menstrual cycles. The primary outcome measure, Daily Record of Severity of Problems (DRSP), established PMS as well as tracked change in five PMS symptoms: psychological, somatic, total symptoms, impact ratings, and worst day ratings. Results: Linear-mixed model analyses indicated both treatments produced comparable reduction in PMS symptoms with medium effect sizes (ES) across all PMS variables as measured by the DRSP (micronutrient ES = 0.50-0.56; B6 ES = 0.43-0.56), with 72% of the micronutrient and 60% of the vitamin B6 group identified as in full remission in PMS symptoms after three cycles. The micronutrient-treated participants showed greater improvement than the B6 group (between group d = 0.51, p < 0.05) in health-related quality of life. For those women (n = 28) who met criteria for premenstrual dysphoric disorder (PMDD), the DRSP ES were larger for those who had been in the micronutrient condition (ES = 1.28-1.67) as compared with those on B6 (ES = 0.50-0.75), although the group differences were not statistically reliable. There were no group differences in side effects, nor any serious adverse effects reported. Conclusions: Both treatments provided similar benefit for reducing PMS symptoms, with greater effect of micronutrients on quality of life as well as potential clinical benefit of micronutrients for PMDD. This study provides further efficacy data on B6 and also identifies the nutritionally broader spectrum intervention as possibly having specific advantages for those whose symptoms are more severe. As this is the first study to investigate these treatments for PMDD, systematic replication is required.

88) Calderón-Guzmán, David, et al. “Pyridoxine, regardless of serotonin levels, increases production of 5-hydroxytryptophan in rat brain.” Archives of medical research 35.4 (2004): 271-274.

89) Hartvig, P., et al. “Pyridoxine effect on synthesis rate of serotonin in the monkey brain measured with positron emission tomography.” Journal of Neural Transmission/General Section JNT 102 (1995): 91-97.

Pretreatment with intravenous pyridoxine hydrochloride 10 mg/kg bodyweight before doing a second PET study resulted in an enhanced rate constant by a mean of 20%. The rate increase was statistically significant. The increase varied considerably in different monkeys from no effect to more than 60%. The effect of pyridoxine on aromatic amino acid decarboxylase activity supported a regulatory role of pyridoxine on the synthesis of neurotransmitter in vivo, and may be of importance in diseases with deficiencies in neurotransmitter function.

90) Vescovi, P. P., et al. “Pyridoxine (Vit. B6) decreases opioids-induced hyperprolactinemia.” Hormone and metabolic research 17.01 (1985): 46-47.

91) Jung, Hyo Young, et al. “Pyridoxine improves hippocampal cognitive function via increases of serotonin turnover and tyrosine hydroxylase, and its association with CB1 cannabinoid receptor-interacting protein and the CB1 cannabinoid receptor pathway.” Biochimica et Biophysica Acta (BBA)-General Subjects 1861.12 (2017): 3142-3153.

92) Al Mughram, Mohammed H., et al. “Elucidating the interaction between pyridoxine 5′-phosphate oxidase and dopa decarboxylase: activation of B6-dependent enzyme.” International Journal of Molecular Sciences 24.1 (2022): 642.

93) Reddy, Pramod. “Preventing Vitamin B6–Related Neurotoxicity.” American Journal of Therapeutics 29.6 (2022): e637-e643.

CBD Cannabidiol for PMS

94) Slavin, Melissa, et al. “Cannabis and symptoms of PMS and PMDD.” Addiction Research & Theory 25.5 (2017): 383-389.

PMS/PMDD and cannabis

Cannabis is a proposed non-hormonal alternative treatment for premenstrual symptoms, potentially offering fewer negative side effects to the current available medications. Little formal research has been done to address the use of cannabis
for women suffering from PMS/PMDD, but it has been suggested as an efficacious and safe alternative treatment for a wide range of women’s conditions including dysmenorrhea (Russo 2002), as well as PMS itself, in doses low enough not
to cause cognitive impairment (Grinspoon & Bakalar 1997). Cannabis has a long medicinal history dating back to cultivation in China in 4000 B.C., where Chinese emperor Chen Nung recommended its use for ‘female disorders’ amongst
many other illnesses (Grinspoon & Bakalar 1997). Anecdotally, cannabis was prescribed by Queen Victoria’s personal physician, Sir John Russell Reynolds, for her menstrual
discomfort throughout her adult life (Russo 2002). After 30 years of experience with cannabis, Reynolds reported that cannabis helped alleviate symptoms associated
with menstruation (Reynolds 1890). Current research has found cannabis to ameliorate a variety of symptoms that overlap with those of PMS and PMDD, including sleep
problems, irritability, depression, and joint pain (Earleywine 2005; Russo et al. 2007; Russo & Hohmann 2013).

95) Ferretti, Morgan L. “The effects of cannabidiol isolate on menstrual-related symptoms.” (2022).

96) Ferretti, Morgan L., et al. “Examination of the effects of cannabidiol on menstrual-related symptoms.” Experimental and Clinical Psychopharmacology (2024).

Some individuals attempt to alleviate menstrual-related symptoms (MRS) by using cannabis and report having expectations that cannabis can improve MRS; however, no study has examined the effect of cannabinoids on MRS. The present study is a pre–post, randomized, open-label trial that aimed to examine the effects of oral cannabidiol (CBD) isolate for alleviating MRS. Participants were assigned randomly to one of two open-label
dosing groups of CBD softgels (160mg twice a day, BID, n=17; 320 mg BID, n=16) and completed a 1-month baseline period. Following baseline, participants were instructed to consume CBD starting the first day they believed they experienced symptoms each month and to take their assigned dose daily for 5 consecutive days for three CBD-consumption months. We examined differences in MRS and related outcomes between baseline and
3 months of CBD consumption. Results revealed reductions (in both dosing groups) in MRS, irritability, anxiety, global impression of change, stress, and subjective severity scores when comparing baseline to all 3 months of CBD consumption. Depression scores did not change in either dosing group. Findings suggest that CBD may have the potential for managing MRS. Importantly, changes in symptoms appeared in the first month of CBD consumption and persisted over the 3 consumption months. Further research is warranted comparing the effects of CBD to placebo (a limitation of the study) and examining the potential to optimize CBD consumption for reducing MRS (e.g., combining CBD with terpenes; varying routes and timing of administration).

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Progestins for Dysfunctional Uterine bleeding

http://www.drnorthrup.com/heavy-menstrual-bleeding-menorrhagia/
97) Heavy Menstrual Bleeding (Menorrhagia) Christiane Northrup, M.D.
Although I prefer to try natural progesterone first, if that doesn’t work, a strong synthetic progestin such as medroxyprogesterone acetate (Provera) can help. (This is the only circumstance in which I recommend the synthetic.) T – See more at: http://www.drnorthrup.com/heavy-menstrual-bleeding-menorrhagia/#sthash.6GlJCGzW.dpuf

98) Maness, David L., et al. “How best to manage dysfunctional uterine bleeding.” Journal of Family Practice 59.8 (2010).

99) Leal, Caio RV, et al. “Abnormal uterine bleeding: The well-known and the hidden face.” Journal of endometriosis and uterine disorders (2024): 100071.

100) Ely, John W., et al. “Abnormal uterine bleeding: a management algorithm.” The Journal of the American Board of Family Medicine 19.6 (2006): 590-602.

101) Jain, Varsha, et al. “Uterine bleeding: how understanding endometrial physiology underpins menstrual health.” Nature reviews endocrinology 18.5 (2022): 290-308.

102) Shoupe, Donna. “The Progestin Revolution: progestins are arising as the dominant players in the tight interlink between contraceptives and bleeding control.” Contraception and Reproductive Medicine 6.1 (2021): 3.

Prospective Observational Study.”

P counteracts E-induced endometrial hyperplasia.

pdf available
103) Munro, Malcolm G., et al. “Oral medroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding: a randomized controlled trial.” Obstetrics & Gynecology 108.4 (2006): 924-929.

104) Bitzer, Johannes, et al. “Medical Management of Heavy Menstrual Bleeding: A Comprehensive Review of the Literature.” Obstetrical & gynecological survey 70.2 (2015): 115-130.

105) Quinn, Stephen, and Jenny Higham. “Available management options for heavy menstrual bleeding.” Prescriber 25.18 (2014): 18-25.

106) Matteson, Kristen A., et al. “Nonsurgical management heavy menstrual bleeding systematic review Nonsurgical management of heavy menstrual bleeding: a systematic review.” Obstetrics & Gynecology 121.3 (2013): 632-643.

107) Matteson, Kristen A., et al. “Practice patterns and attitudes about treating abnormal uterine bleeding: a national survey of obstetricians and gynecologists.” American journal of obstetrics and gynecology 205.4 (2011): 321-e1.

108) Kaunitz, A. M., et al. “Levonorgestrel-releasing intrauterine system or medroxyprogesterone for heavy menstrual bleeding: a randomized controlled trial.” Obstetrics and gynecology 116.3 (2010): 625.

109) Managing acute heavy menstrual bleeding
Recommendations for hormonal regimens to halt blood loss in the outpatient
January 01, 2014 By Anita L. Nelson, MD

110) Aksu, M. Feridun, et al. “High‐Dose Medroxyprogesterone Acetate for the Treatment of Dysfunctional Uterine Bleeding in 24 Adolescents.” Australian and New Zealand journal of obstetrics and gynaecology 37.2 (1997): 228-231.

Menorrhagia, irregular bleeding

Vitamin A for Uterine Bleeding – More than Just Fibroids !!!

111) Lithgow, DM* & Politzer, WM. “Vitamin A in the treatment of menorrhagia.” South African Medical Journal 51.7 (1977): 191-193.
Hypovitaminosis A was found to be an important cause of menorrhagia, and a statistically significant difference between the fasting serum vitamin A values of healthy controls and patients with menorrhagia was noted. Vitamin A is a co-factor of 3,B-dehydrogenase in steroidogenesis and deficiencies of this vitamin may result in impaired enzyme activiiy. The level of endogenous 17Beta-oestradiol appears to be elevated with vitamin A therapy, and menorrhagia was alleviated in more than 92% of patients.

Table 11 details the causes of menorrhagia in 174 patients. Vitamin A deficiency appeared to be the major aetiological factor in 43,68% of these women. The aetiology was unknown in 17,24%. A number of patients (11,49%) had previously been subjected to sterilization. Pyridoxine (vitamin B.) deficiency was found in 9,77% and was diagnosed clinically’··11 and subsequently biochemically.” Eight patients with both vitamin B. and vitamin A deficiency were classified as vitamin A-deficient. The causative factors most frequently observed were deficient diet, malabsorption, recent infections, overexposure to sunlight” and excessive intake of alcohol.”

The rise in 17,Beta-oestradiol following vitamin A therapy (Table Ill) is significant, since graphs of the menstrual cycle indicate an association in the peaks of 17f3 -oestradiol and vitamin A.”,’4 Should vitamin A fail to raise oestradiol levels or alleviate menorrhagia, then checks for hypoproteinaemia, vitamin E (which improves vitamin A storage and utilization)” and zinc (required to mobilize hepatic vitamin A)’” are indicated.

Vitamin A (retinol) deficiency decreaes estrogen production

Uterine Bleeding Rx:
MK7 Vitamin K
Vitamin A (retinol) 25,000 iu BID
or 100000 IU vitamin A per day for 15 day.
Vitamin E
Zinc

Dysfunctional Uterine Bleeding DUB

112) Maness, David L., et al. “How best to manage dysfunctional uterine bleeding.” Journal of Family Practice 59.8 (2010).

113) Leal, Caio RV, et al. “Abnormal uterine bleeding: The well-known and the hidden face.” Journal of endometriosis and uterine disorders (2024): 100071.

114) Ely, John W., et al. “Abnormal uterine bleeding: a management algorithm.” The Journal of the American Board of Family Medicine 19.6 (2006): 590-602.

115) Jain, Varsha, et al. “Uterine bleeding: how understanding endometrial physiology underpins menstrual health.” Nature reviews endocrinology 18.5 (2022): 290-308.

116) Shoupe, Donna. “The Progestin Revolution: progestins are arising as the dominant players in the tight interlink between contraceptives and bleeding control.” Contraception and Reproductive Medicine 6.1 (2021): 3.

117) Kader, Mohammad Irfan Abdul, V. Karthikeyan, and J. Sabitha. “A Comparative Study On Efficacy of Norethisterone and Medroxyprogestrone in The Management of Dysfunctional Uterine Bleeding: A

(118) Dikke, Galina B., et al. “Experience of treating patients with abnormal uterine bleeding associated with ovulatory dysfunction.” Obstetrics and Gynecology 3 (2024): 142-152.

Abnormal uterine bleeding (AUB) associated with ovulatory disfunction (OD) is the most common finding among women with chronic AUB, accounting for 57.7% of cases. Oral progestogens are often prescribed for irregular and copious menstruation. However, a course of hormonal rehabilitation after AUB-OD may not be enough. Inositols have been shown to be highly effective in restoring ovulation, normalizing the menstrual cycle, correcting carbohydrate and lipid metabolism, and reducing body weight.

Objective: To evaluate the effectiveness of complex treatment consisting of a combination of gestagen, iron medication and complex containing myoinositol, D-chiroinositol (5:1), folic acid and manganese in reproductive-aged patients with abnormal uterine bleeding associated with type I–III ovulatory dysfunction.

Materials and methods: The multicentre study in real clinical practice included 2,042 women with OD. The patients received dydrogesterone or micronized progesterone for 3 cycles (from 14 to 25 days), a medication containing myoinositol 1000 mg, D-chiroinositol 200 mg, folic acid 200 mg, manganese 5 mg (Dikirogen) for 6 cycles, iron sulfate/ascorbic acid for 3–4 months (according to indications). The parameters of the menstrual cycle (MC), hemoglobin, serum ferritin, and body weight were assessed at 3, 6 and 12 months from the start of treatment.

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Fibroids

119) Bai, Tao, et al. “The combination of natural compounds Crila and epigallocatechin gallate showed enhanced antiproliferative effects on human uterine fibroid cells compared with single treatments.” F&S Science 4.4 (2023): 341-349.

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Post-Partum Depression

120) Barnes, Kylie N., Claire M. Vogl, and Leigh Anne Nelson. “Zuranolone: The first FDA-approved oral treatment option for postpartum depression.” Annals of Pharmacotherapy 58.7 (2024): 728-734.

121) Reddy, Doodipala Samba, Robert H. Mbilinyi, and Emily Estes. “Preclinical and clinical pharmacology of brexanolone (allopregnanolone) for postpartum depression: a landmark journey from concept to clinic in neurosteroid replacement therapy.” Psychopharmacology 240.9 (2023): 1841-1863.

122) Kargbo, Robert B. “Neurosteroids and Postpartum Depression: The Mechanism, Efficacy, and Approval of Brexanolone and Zurzuvae.” ACS Medicinal Chemistry Letters 14.10 (2023): 1326-1328.

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Progesterone Allergic Hypersensitivity

123) Azadi, Negar, et al. “Effect of progesterone administration on tissue mast cell population and histamine content in mice uterus after ovulation induction.” JBRA Assisted Reproduction 27.3 (2023): 436.

124) Uchida, Hitoshi, et al. “Neurosteroid-induced hyperalgesia through a histamine release is inhibited by progesterone and p, p′-DDE, an endocrine disrupting chemical.” Neurochemistry international 42.5 (2003): 401-407.

125) Mittman, Robert J., et al. “Progesterone-responsive urticaria and eosinophilia.” Journal of allergy and clinical immunology 84.3 (1989): 304-310.

126) Vliagoftis, Harissis, Violetta Dimitriadou, and Theoharis C. Theoharides. “Progesterone triggers selective mast cell secretion of 5-hydroxytryptamine.” International Archives of Allergy and Immunology 93.2-3 (1990): 113-119.

127) Jo, Eun-Jung, Seung-Eun Lee, and Hye-Kyung Park. “Clinical characteristics of exogenous progestogen hypersensitivity.” Asian Pacific Journal of Allergy and Immunology 37.3 (2019): 183-187.

Results: Nine patients had exogenous PH. Six patients were treated with progesterone for threatened abortion, and three for ARTs. Their mean age was 33.6 years, and their mean body mass index was 26.3 kg/m2. They had never experienced an adverse drug reaction. The mean latency to symptom onset was 5.8 days (range 1 h to 11 days). The patients complained of hives, erythema and itching, and one developed anaphylaxis. All patients were treated with antihistamines, and six patients were treated with systemic corticosteroids. Epinephrine was administered to one patient with hypotension. The symptom duration was 1-14 days. Skin tests were performed in four patients; all were positive. Two patients were treated successfully by progesterone desensitization.
Conclusions: The clinical features of exogenous PH were similar to those of type I hypersensitivity reactions, but tended to develop later and did not respond to antihistamines or steroids. As use of progesterone increases, an understanding of the
clinical features of exogenous PH becomes ever-more important

128) Sandru, Florica, et al. “Progesterone Hypersensitivity in Assisted Reproductive Technologies: Implications for Safety and Efficacy.” Journal of Personalized Medicine 14.1 (2024): 79.

130) Sashidhar, Nivedita, Venkataram Mysore, and G. V. Thejavathy. “Exogenous Progestogen Hypersensitivity and its Increasing Association with Assisted Reproductive Techniques (ART)/in vitro Fertilization (IVF).” Indian Dermatology Online Journal 15.1 (2024): 24-32.

131) Jensen, Federico, et al. “Estradiol and progesterone regulate the migration of mast cells from the periphery to the uterus and induce their maturation and degranulation.” PloS one 5.12 (2010): e14409.

132) Bernstein, I. Leonard, et al. “A case of progesterone-induced anaphylaxis, cyclic urticaria/angioedema, and autoimmune dermatitis.” Journal of Women’s Health 20.4 (2011): 643-648.

Progesterone protection in ALS

133) Deniselle, Maria Claudia Gonzalez, et al. “Basis of progesterone protection in spinal cord neurodegeneration.” The Journal of steroid biochemistry and molecular biology 83.1-5 (2002): 199-209.

134) Kolatorova, Lucie, et al. “Progesterone: a steroid with wide range of effects in physiology as well as human medicine.” International Journal of Molecular Sciences 23.14 (2022): 7989.

Amyotrophic lateral sclerosis is a motor neuron disease and, after Alzheimer’s disease and Parkinson’s disease, is the third most common neurodegenerative disorder. PROG has been implicated in various neuroprotective properties, of which longevity [236], muscle strength [237], cell health [238], lowered oxidative stress in the spinal cord, and nitric oxide [236,239] are the most relevant. It has been shown to increase brain-derived neurotrophic factor [237] and normalizes mRNA levels in components of the sodium-potassium pump, which is important for cell nutrition and neurotransmission and is also crucial for mitochondrial health [239]. Moreover, PROG was observed to inhibit the activity of astrocytes, which have predominately deleterious effects in the context of amyotrophic lateral sclerosis because they correspond to increased inflammation. PROG also protects against glutamate excitotoxicity in vitro, one of the major sources of pathology in amyotrophic lateral sclerosis [40]. Synthetic 19-norprogesterone derivatives may also play a role in attenuating motoneuron degeneration and thus have potential in amyotrophic lateral sclerosis treatment [218].

135) De Nicola, Alejandro F., et al. “Progesterone and allopregnanolone neuroprotective effects in the wobbler mouse model of amyotrophic lateral sclerosis.” Cellular and Molecular Neurobiology 42.1 (2022): 23-40.

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************** Progesterone as Anti-Inflammatory Drug ******************************

136) Fedotcheva, Tatiana A., Nadezhda I. Fedotcheva, and Nikolai L. Shimanovsky. “Progesterone as an anti-inflammatory drug and immunomodulator: new aspects in hormonal regulation of the inflammation.” Biomolecules 12.9 (2022): 1299.

137) Al‐Kuraishy, Hayder M., et al. “New insights on the potential effect of progesterone in Covid‐19: Anti‐inflammatory and immunosuppressive effects.” Immunity, Inflammation and Disease 11.11 (2023): e1100.

P4 active metabolite allopregnanolone is regarded as a neurosteroid that acts as a positive modulator of γ‐aminobutyric acid (GABAA) so it may reduce neuropsychiatric manifestations and dysautonomia in COVID‐19 patients. Conclusion: Taken together, the anti‐inflammatory and immunomodulatory properties of P4 may improve central and peripheral complications in COVID‐19.\

Pregnenolone

138) Balan, Irina, et al. “Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders.” Life 14.5 (2024): 582.

Pregnane neuroactive steroids, notably allopregnanolone and pregnenolone, exhibit efficacy in mitigating inflammatory signals triggered by toll-like receptor (TLR) activation, thus attenuating the production of inflammatory factors. Clinical studies highlight their therapeutic potential, particularly in conditions like postpartum depression (PPD), where the FDA-approved compound brexanolone, an intravenous formulation of allopregnanolone, effectively suppresses TLR-mediated inflammatory pathways, predicting symptom improvement. Additionally, pregnane neurosteroids exhibit trophic and anti-inflammatory properties, stimulating the production of vital trophic proteins and anti-inflammatory factors. Androstane neuroactive steroids, including estrogens and androgens, along with dehydroepiandrosterone (DHEA), display diverse effects on TLR expression and activation. Notably, androstenediol (ADIOL), an androstane neurosteroid, emerges as a potent anti-inflammatory agent, promising for therapeutic interventions. The dysregulation of immune responses via TLR signaling alongside reduced levels of endogenous neurosteroids significantly contributes to symptom severity across various neuropsychiatric disorders. Neuroactive steroids, such as allopregnanolone, demonstrate efficacy in alleviating symptoms of various neuropsychiatric disorders and modulating neuroimmune responses, offering potential intervention avenues. This review emphasizes the significant therapeutic potential of neuroactive steroids in modulating TLR signaling pathways, particularly in addressing inflammatory processes associated with neuropsychiatric disorders. It advances our understanding of the complex interplay between neuroactive steroids and immune responses, paving the way for personalized treatment strategies tailored to individual needs and providing insights for future research aimed at unraveling the intricacies of neuropsychiatric disorders.

Neuroactive steroids are synthesized within both endocrine glands and the brain. In the brain, neurons are the primary producers of neurosteroids [14,15,16,17,18,19,20]. Neuroactive steroids, synthesized from cholesterol, can be classified into three categories: pregnane, androstane, and sulfated neuroactive steroids.

Pregnanes, including allopregnanolone, pregnanolone, and 3α,5α-THDOC, act as positive modulators of GABAA receptor subtypes. These compounds enhance inhibitory neurotransmission mediated by GABAA receptors, leading to anxiolysis, sedation, anti-convulsant activity, and the enhancement of inhibitory circuits in the brain [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35]. Importantly, their anti-inflammatory actions are distinct from their GABAergic mechanisms [36,37,38].

Preclinical and clinical studies have highlighted reduced levels of pregnane neuroactive steroids, such as pregnenolone and allopregnanolone, in conditions like stress, depression, post-traumatic stress disorder (PTSD), and alcohol use disorder (AUD)

Allopregnanolone and its precursors, pregnenolone and progesterone, have shown promise in animal models of AUD, chronic stress-induced depression, traumatic brain injury (TBI), multiple sclerosis (MS), and Alzheimer’s disease (AD)

In clinical studies, progesterone has demonstrated efficacy in TBI and cocaine craving, while pregnenolone has shown benefits in alcohol and cannabis use disorders, and allopregnanolone has been effective in treating postpartum depression (PPD)

Clinical observations further support the therapeutic potential of compounds like brexanolone, a Food and Drug Administration (FDA)-approved intravenous formulation of allopregnanolone, in conditions such as PPD, attributed to their inhibition of TLR inflammatory pathways

pregnane neuroactive steroids, possess anti-inflammatory properties that operate independently of their effects on GABAA receptors. This suggests potential mitigation of excessive TLR signaling and the related inflammatory and neuroinflammatory conditions.

Post-Finasteride Syndrome – loss of libido and suicide

139) Pinna, Graziano. “Allopregnanolone, the neuromodulator turned therapeutic agent: thank you, next?.” Frontiers in endocrinology 11 (2020): 236.

Collectively, these and many more observations in the field by many talented neurosteroid scientists, led to clinical trials that demonstrated the efficacy of intravenous allopregnanolone in postpartum depression (40, 41). Given the remarkable pharmacological efficacy of this novel therapeutic, on March
19th, 2019, the FDA approved intravenous allopregnanolone (i.e., brexanolone) as the first specific treatment for postpartum depression (Figure 1)

Pharmacological treatments, including finasteride and oral contraceptives, that inhibit 5a-RI, which results in a blood and brain allopregnanolone decrease also affect subunit expression of GABAA receptor and are associated with mood symptoms and suicide and are part of postfinasteride syndrome (57, 58). Post-finasteride syndrome, in addition to depression, anxiety and cognitive deficits also induces sexually-related side effects, such as loss of libido, erectile dysfunction, decreased arousal and difficulty in achieving an orgasm that persist despite drug withdrawal
(58).

Brexanolone is superior to traditional antidepressants in the treatment of mood disorders

Following this concept, brexanolone, a b-cyclodextrinbased parenterally-administered soluble formulation of allopregnanolone, was developed and FDA-approved for treating post-partum depression. In an open-label study, a single brexanolone IV administration showed rapid and
long-lasting antidepressant effects in severe post-partum depression (40).

140) Pinna, Graziano. “Role of PPAR-allopregnanolone signaling in behavioral and inflammatory gut-brain axis communications.” Biological Psychiatry 94.8 (2023): 609-618.

Both PPAR-α and allopregnanolone are abundantly expressed in the colon and they exert potent anti-inflammatory actions by blocking toll-like receptor-4-NFkB pathway in peripheral immune cells, neurons, and glia. The perspective that PPAR-α regulation in the colon by gut microbiota or metabolites influences central allopregnanolone content after trafficking to the brain -thereby serving as a mediator of gut-brain axis communications- is examined.

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!!!!!!!!!!!!Inflammatory IL-6 Reduces Allopregnanaolone Synthesis in Brain !!!!!!!!!!!!!!!!

141) Parks, Eileen E., et al. “Interleukin 6 reduces allopregnanolone synthesis in the brain and contributes to age-related cognitive decline in mice.” Journal of Lipid Research 61.10 (2020): 1308-1319.

Furthermore, our results indicate that AlloP is a critical link between inflammatory cytokines and the age-related decline in cognitive function.

!!!!!!!!!!!!!!!!!!!!!!!!!! Anti Cancer effects !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

142) Zamora-Sánchez, Carmen J., and Ignacio Camacho-Arroyo. “Allopregnanolone: Metabolism, Mechanisms of Action, and Its Role in Cancer.” International Journal of Molecular Sciences 24.1 (2022): 560.

Recently the study of 3-Alpha-THP [Allopregnanolone] has indicated that low physiological concentrations of this metabolite induce the progression of several types of cancer, such as breast, ovarian, and glioblastoma, while high concentrations inhibit it. In this review, we explore current knowledge on the metabolism and mechanisms of action of 3-THP in normal and tumor cells.

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Progesterone Pre-operatively Protects Against Breast Cancer

143) Hrushesky, WilliamJ M., Avrum Z Bluming, and ScottA Gruber. “Menstrual influence on surgical cure of breast cancer.” The Lancet 335.8695 (1990): 984.

In a retrospective study of 44 premenopausal women who underwent resection of a primary breast cancer and were followed for 5 to 12 years, disease recurrence and metastasis were more frequent and more rapid in women who had been operated upon during the perimenstrual period (days 0-6 and 21-36 of the menstrual cycle). By multivariate analysis, the time of resection in relation to the menstrual cycle is an independent predictor of the likelihood of future metastatic disease. Patients who underwent resection during the perimenstrual period had a more than quadrupled risk of recurrence and death compared with women operated upon during days 7 to 20 of the menstrual cycle.

Mouse Study

144) Ratajczak, H. V., R. B. Sothern, and W. J. Hrushesky. “Estrous influence on surgical cure of a mouse breast cancer.” The Journal of experimental medicine 168.1 (1988): 73-83.

However, estrous stage at time of surgical removal ofthe tumor, as reflected by cell types in vaginal smear, markedly affected whether or not metastases ultimately appeared. Because the estrous cycle in mice, comparable to the human menstrual cycle, reflects high-amplitude, rhythmic changes in hormone concentrations, it may be that the hormonal status of a woman at the time of tumor resection is an important determinant of whether or not that breast cancer ultimately metastasizes.

145) Badwe, R. A., et al. “Timing of surgery during menstrual cycle and survival of premenopausal women with operable breast cancer.” The Lancet 337.8752 (1991): 1261-1264.

Timing of operation in relation to menstrual phase might affect outlook in premenopausal women with operable breast cancer. We examined the records of 249 such women treated between 1975 and 1985, and compared overall and recurrence-free survival in those whose operation was 3-12 days after their last menstrual period (LMP) (group 1, n=75) with those in whom it was 0-2 or 13-32 days after LM P (group 2, n=174). Overall and recurrence-free survival were greatly reduced in group 1 women (p<0·001 for both). Actuarial survival at 10 years was 54% in group 1 versus 84% in group 2. This effect was independent of other factors, was of much the same importance as nodal status in multivariate analysis, was largely confined to histologically node-positive cases, seemed to be greater in women with small tumours (≤2 cm), and was seen in patients with oestrogen-receptor positive and negative tumours. Thus phase of menstrual cycle at operation is of great importance for long-term outlook in premenopausal women with breast cancer.

146) Badwe, R. A., et al. “Serum progesterone at the time of surgery and survival in women with premenopausal operable breast cancer.” European Journal of Cancer 30.4 (1994): 445-448.
Serum progesterone and oestradiol levels have been measured in 210 premenopausal women with operable breast cancer on samples taken within 3 days of tumour excision. There was no relation between oestradiol level and time since last menstrual period, nor any effect of oestradiol value on prognosis. However, serum progesterone levels were related to the phase of the cycle as determined by time since last menstrual period. When divided on a basis of levels > 1.5 ng/ml (luteal phase) and < or = 1.5 ng/ml, it was found that there was no difference in survival between the two groups among 117 axillary node negative cases. However, in the 93 patients with positive axillary nodes, higher progesterone levels were associated with significantly better survival. Thus, serum progesterone levels at the time of surgery may affect the prognosis of premenopausal node positive patients with operable breast cancer.

147) Badwe, Rajendra, et al. “Single-Injection Depot Progesterone Before Surgery and Survival in Women With Operable Breast Cancer: A Randomized Controlled Trial.” (2011).
In 471 node-positive patients, the 5-year DFS [Disease Free Survival] and OS [Overall survival] rates in the progesterone group versus control group were 65.3% v 54.7% (HR, 0.72; 95% CI, 0.54 to 0.97; P .02) and 75.7% v 66.8% (HR, 0.70; 95% CI, 0.49 to 0.99; P .04), respectively. In multivariate analysis, DFS was significantly improved with progesterone in node-positive patients (adjusted HR, 0.71; 95% CI, 0.53 to 0.95; P .02), whereas there was no significant effect in node-negative patients (P for interaction .04).

148) Pujol, Pascal, et al. “A prospective prognostic study of the hormonal milieu at the time of surgery in premenopausal breast carcinoma.” Cancer: Interdisciplinary International Journal of the American Cancer Society 91.10 (2001): 1854-1861.

149) Zhang, Baoning. “Prognosis of patients with breast cancer related to the timing of operation during menstruaZl cycle.” Chinese Journal of Cancer Research 10 (1998): 138-142.
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Progesterone Beneficial in glioblastoma

150) Atif, Fahim, et al. “Progesterone treatment attenuates glycolytic metabolism and induces senescence in glioblastoma.” Scientific reports 9.1 (2019): 988.

We examined the effect of progesterone treatments on glycolytic metabolism and senescence as possible mechanisms in controlling the growth of glioblastoma multiforme (GBM). In an orthotopic mouse model, after tumor establishment, athymic nude mice received treatment with progesterone or vehicle for 40 days. Compared to controls, high-dose progesterone administration produced a significant reduction in tumor size (~47%) and an increased survival rate (~43%) without any demonstrable toxicity to peripheral organs (liver, kidney). This was accompanied by a significant improvement in spontaneous locomotor activity and reduced anxiety-like behavior. In a follow-up in vitro study of U87MG-luc, U87dEGFR and U118MG tumor cells, we observed that high-dose progesterone inhibited expression of Glut1, which facilitated glucose transport into the cytoplasm; glyceraldehyde 3-phosphate dehydrogenase (GAPDH; a glycolysis enzyme); ATP levels; and cytoplasmic FoxO1 and Phospho-FoxO1, both of which control glycolytic metabolism through upstream PI3K/Akt/mTOR signaling in GBM. In addition, progesterone administration attenuated EGFR/PI3K/Akt/mTOR signaling, which is highly activated in grade IV GBM. High-dose progesterone also induced senescence in GBM as evidenced by changes in cell morphology and β-galactocidase accumulation. In conclusion, progesterone inhibits the modulators of glycolytic metabolism and induces premature senescence in GBM cells and this can help to reduce/slow tumor progression.

151) Luo, Hui, et al. “Prognostic value of progesterone receptor expression in ovarian cancer: a meta-analysis.” Oncotarget 8.22 (2017): 36845.

• In order to address the disagreement of progesterone receptor in ovarian cancer survival, we conducted this meta-analysis. …CONCLUSION: Progesterone receptor expression can be used as a favorable prognostic predictor in ovarian cancer m …

152) Progesterone decreases ovarian cancer cells migration and invasion.Lima MA,
Silva SV, Jaeger RG, Freitas VM.Steroids. 2020 Sep;161:108680. doi: 10.1016/j.steroids.2020.108680. Epub 2020 Jun 18.PMID: 32562708

• Also, progesterone is involved in antitumorigenic process in different types of cancer. …Our results suggest that progesterone interferes with migration and invasion of ovarian cells. …

https://www.pnas.org/doi/full/10.1073/pnas.2013595117
153) Kim, Olga, et al. “Targeting progesterone signaling prevents metastatic ovarian cancer.” Proceedings of the National Academy of Sciences 117.50 (2020): 31993-32004.

Abstract
Effective cancer prevention requires the discovery and intervention of a factor critical to cancer development. Here we show that ovarian progesterone is a crucial endogenous factor inducing the development of primary tumors progressing to metastatic ovarian cancer in a mouse model of high-grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer type. Blocking progesterone signaling by the pharmacologic inhibitor mifepristone or by genetic deletion of the progesterone receptor (PR) effectively suppressed HGSC development and its peritoneal metastases. Strikingly, mifepristone treatment profoundly improved mouse survival (∼18 human years). Hence, targeting progesterone/PR signaling could offer an effective chemopreventive strategy, particularly in high-risk populations of women carrying a deleterious mutation in the BRCA gene.

153) Tamburello, Mariangela, et al. “Preclinical evidence of progesterone as a new pharmacological strategy in human adrenocortical carcinoma cell lines.” International Journal of Molecular Sciences 24.7 (2023): 6829.
Here, we deepen the role of progesterone as a new potential drug for ACC, in line with its antitumoral effect in other cancers. Methods: NCI-H295R, MUC-1, and TVBF-7 cell lines were used and xenografted in zebrafish embryos. Migration and invasion were studied using transwell assays, and MMP2 activity was studied using zymography. Apoptosis and cell cycle were analyzed by flow cytometry. Results: Progesterone significantly reduced xenograft tumor area and metastases formation in embryos injected with metastatic lines, MUC-1 and TVBF-7. These results were confirmed in vitro, where the reduction of invasion was mediated, at least in part, by the decrease in MMP2 levels. Progesterone exerted a long-lasting effect in metastatic cells. Progesterone caused apoptosis in NCI-H295R and MUC-1, inducing changes in the cell-cycle distribution, while autophagy was predominantly activated in TVBF-7 cells. Conclusion: Our results give support to the role of progesterone in ACC. The involvement of its analog (megestrol acetate) in reducing ACC progression in ACC patients undergoing EDP-M therapy is now under investigation in the PESETA phase II clinical stud

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

154) Mohamed, Omyma Shehata, et al. “Cytoprotective effect and clinical outcome of perioperative progesterone in brain tumors, a randomized microscopically evidence study.” Egyptian Journal of Anaesthesia 38.1 (2022): 466-475.
—————————

155) Fedotcheva, Tatiana A., Nadezhda I. Fedotcheva, and Nikolai L. Shimanovsky. “Progestins as anticancer drugs and chemosensitizers, new targets and applications.” Pharmaceutics 13.10 (2021): 1616.

156) Mohammed, Hisham, et al. “Progesterone receptor modulates ERα action in breast cancer.” Nature 523.7560 (2015): 313-317.

We conclude that activation of PR results in a robust association between PR and the ERα complex.

Progesterone blocks ERα+ tumour growth

PR is a critical determinant of ERα function due to crosstalk between PR and ERα. In this scenario, under estrogenic conditions, an activated PR functions as a proliferative brake in ERα+ breast tumours by re-directing ERα chromatin binding and altering the expression of target genes that induce a switch from a proliferative to a more differentiated state 6.

Progesterone receptor (PR) expression is employed as a biomarker of estrogen receptor-α (ERα) function and breast cancer prognosis. We now show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited estrogen-mediated growth of ERα+ cell line xenografts and primary ERα+ breast tumour explants and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PgR is a common feature in ERα+ breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.

There is compelling evidence that inclusion of a progestogen as part of hormone replacement therapy (HRT) increases risk of breast cancer, implying that PR signalling can contribute towards tumour formation1. However, the increased risk of breast cancer associated with progestogen-containing HRT is mainly attributed to specific synthetic progestins, in particular medroxyprogesterone acetate (MPA), which is known to also have androgenic properties2. The relative risk is not significant when native progesterone is used3. In ERα+ breast cancers, PR is often used as a positive prognostic marker of disease outcome4, but the functional role of PR signalling remains unclear. While activation of PR may promote breast cancer in some women and in some model systems, progesterone treatment has been shown to be antiproliferative in ERα+ PR+ breast cancer cell lines5-7 and progestogens have been shown to oppose estrogen-stimulated growth of an ERα+ PR+ patient-derived xenograft8. In addition, exogenous expression of PR in ERα+ breast cancer cells blocks estrogen-mediated proliferation and ERα transcriptional activity9. Furthermore, in ERα+ breast cancer patients, PR is an independent predictor of response to adjuvant tamoxifen10, high levels of PR correlate with decreased metastatic events in early stage disease11 and administration of a progesterone injection prior to surgery can provide improved clinical benefit12. These observations imply that PR activation in the context of estrogen-driven, ERα+ breast cancer, can have an anti-tumourigenic effect. In support of this, PR agonists can exert clinical benefit in ERα+ breast cancer patients that have relapsed on ERα antagonists13.

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155) deleted

!!!!!!!!!!!!!!!!!!!!!!! Declining Progesterone Luteal Phase Causes PMS !!!!!!!!!!!!!!!!!!!!!!!!!!!!

156) Roomruangwong, Chutima, et al. “Lowered plasma steady-state levels of progesterone combined with declining progesterone levels during the luteal phase predict peri-menstrual syndrome and its major subdomains.” Frontiers in psychology 10 (2019): 488965.

We recruited 41 participants by word of mouth, 21 women without subjective complaints of PMS and 20 women with subjective complaints of PMS.

Discussion: The first major finding of the current study is that lowered steady state levels of sex hormones, mainly progesterone and to a lesser degree also oestradiol, when averaged over the menstrual cycle, predicted the presence of PMS as well as its severity….when plasma levels of progesterone decline in the luteal phase (the week prior to DRSP measurements) severity of PMS is worse…Moreover, blocking the conversion of progesterone to its metabolite using the 5α-reductase inhibitor dutasteride mitigates symptoms of PMDD (Martinez et al., 2016).

These results suggest that PMS is related to lower progesterone concentrations during the second half of the menstrual cycle, which is described as “corpus luteum insufficiency,” and is considered to result from suboptimal pre-ovulatory follicular development (Dawood, 1994; Hinney et al., 1996). Deficient progesterone production is a condition that may lead to inadequate maintenance of a regular secretory endometrium and, therefore, may be associated with recurrent pregnancy loss and infertility, although up to 10% of fertile women also show corpus luteum insufficiency (Sonntag and Ludwig, 2012). This condition may be due to a functional inadequacy of the hypothalamic-pituitary secretion of gonadotrophins, or may otherwise occur in patients suffering from the polycystic ovary syndrome (PCOS) (Barthelmess and Naz, 2014). Whereas the former may be related to external factors, including exposure to environmental xeno-oestrogens, the latter is commonly associated with insulin resistance and metabolic disturbance.

Our results show that changes in sex hormones during the menstrual cycle and lowered steady state levels of these hormones determine increased peri-menstrual symptoms and increased ratings during the cycle, rather than “premenstrual” symptoms.

The classic-school allopathic approach to treatment of patients suffering from PMS recommends suppressing ovulation by a combined oral contraceptive. However, this approach does commonly not relief the symptoms, which is part is related to the type of progestagen used, with drospirenone possibly being preferable (Nevatte et al., 2013). For example, in a subgroup of patients, hormonal contraceptive pills, despite of suppressing the ovulation, may increase PMS-like symptoms (e.g., irritability, depression, anxiety, bloating, fatigue, and breast tenderness) (Oinonen and Mazmanian, 2002). Overall, progesterone treatment studies did not reveal an efficacy of progesterone to treat PMS or PMDD (Freeman et al., 1990; Ford et al., 2012). In addition, more than half of women who started taking hormonal contraceptives discontinue these drugs within the first year due to side effects including PMS-like symptoms (Berenson et al., 1997; Rosenberg and Waugh, 1998; Doyle et al., 2007). Other studies showed that cyclical and continuous progestogen treatment may induce PMS-like symptoms (Baker and O’Brien, 2012).

Conclusion

In conclusion, the cumulative effects of lowered steady state levels of progesterone in the luteal phase combined with (lagged) changes in progesterone in the luteal phase predict total DRSP scores as well as its four main dimensions (namely depression, physio-somatic symptoms, breast tenderness and appetite, anxiety) and, therefore, the diagnosis of peri-menstrual syndrome. Classical diagnoses of PMS are less adequate, whereas two new diagnoses developed in the current study are externally validated by the biomarkers, namely (a) a diagnosis of peri-menstrual syndrome denoting individuals with increased symptoms in the pre and post-menstrual period; and (b) a diagnosis of menstrual cycle-associated symptoms (MCAS) denoting subjects who experience increased DRSP symptoms all over the cycle. Therefore, future research should examine the associations of biomarkers with those two diagnoses and with changes over time in the DRSP (and its four dimensions), which provides more information on the steady state (increased scores all over the cycle) and cyclical nature (peri-menstrual) of the syndromes.

Conclusion: A significant increase in menstrual-cycle related symptoms can best be conceptualized as “peri-menstrual syndrome” and may result from insufficient progesterone production (relative corpus luteum insufficiency), which, in part may result from lowered oestradiol production indicating suboptimal pre-ovulatory follicular development.

157) Dalton, Katharina. “Points: Treating the premenstrual syndrome.” BMJ: British Medical Journal 297.6646 (1988): 490.

158) Dalton, Katharina. “What is this PMS?.” The Journal of the Royal College of General Practitioners 32.245 (1982): 717.

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159) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.

160) Horbatiuk, Olha, et al. “Using micronized progesterone for treatment of premenopausal age women suffering from severe premenstrual syndrome.” Current Issues in Pharmacy and Medical Sciences 30.3 (2017): 138-141.

161) Berger, Miles, John A. Gray, and Bryan L. Roth. “The expanded biology of serotonin.” Annual review of medicine 60.1 (2009): 355-366.

162) Kumar, Pratap, and Navneet Magon. “Hormones in pregnancy.” Nigerian Medical Journal 53.4 (2012): 179-183.

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Diagnosis and Treatment of Premenstrual Syndrome Part Three

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