HIGHER PREVALENCE OF “LOW T3 SYNDROME” IN PATIENTS WITH CHRONIC FATIGUE SYNDROME: A CASE-CONTROL STUDY


Begoña Ruiz-Núñez, Rabab Tarasse, Emar F Vogelaar, D A Janneke Dijck-Brouwer, Frits A J Muskiet PMID: 29615976, PMCID: PMC5869352, DOI:10.3389/fendo.2018.00097, Front Endocrinol (Lausanne), 2018 Mar 20;9:97. doi: 10.3389/fendo.2018.00097. 2018.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869352/

RE. THIS ARTICLE: in my opinion “low T3 syndrome” is a synonym for Functional Hypothyroidism. If I am correct, people with the symptoms of low T3 syndrome should have a “Thyroid Profile” done, with tests for TSH, free T4, free T3 and reverse T3: if the T3/rT3 ratio turns out to be less than 20, they should be treated with T3, using the usual protocol.
If treatment is successful, the functional hypothyroidism will be eliminated, “low thyroid” symptoms will disappear and to all intents and purposes, their CFS will be CURED !
G.A.Harry.

IMAGINE TWIN CHIMPANZEES:


A PARABLE ON HEALTHY AGING

ONCE UPON A TIME THERE WERE TWO CHIMPANZEES:
they were twins, but one was smart and the other, not so very.

On their third birthday each was given a toolbox, with a screwdriver, pliers, a hammer, a saw, a crowbar and a big knife.

The smart Chimp opened his toolbox and found that he could use the tools, lifting stones to find delicious worms, getting termites from their nests, opening walnuts, cutting coconuts, peeling oranges, squeezing things and generally making life easier for himself. He kept the toolbox in a dry spot inside his cave, took it with him everywhere and used the tools often, always cleaning and returning them to the box after use.

The unsmart brother loved his toolbox because it was the first birthday present that he could remember, but he never opened it and often left it out In the rain.

When they were about 26 years old, each somehow, on the same day, got caught in a trap set by a trapper who suffered from carpenteric dyslexia:
he made all his traps with autolocking doors, but he put the hinges on the inside.

The smart Chimp immediately noticed that his screwdriver would fit the screws which held the hinges and couldn’t keep his amusement down.
He sat for a while, giggling, then disconnected the door, put his ‘driver back into its box and walked out.

He tried to set his brother free, but couldn’t reach the hinges, the cage was made of steel, the crowbar wasn’t strong enough and the spaces between the bars were too narrow to let the screwdriver through, so he gave up trying.

He told the unsmart Chimp to open his toolbox but when he did, he found that the 26-year-old tools had rusted and stuck firmly together: he couldn’t even get them out of the toolbox.

The smart Chimp took his toolbox back to his cave and lived happily ever after, using his tools often and keeping them in good condition.

The unsmart Chimp was sold to a zoo, where he died at 33 from Alzheimer’s disease.

Q: WHAT’S THE POINT OF THIS IDIOTIC STORY ?

A: LOSS OF OUR HORMONAL “TOOLS”MAY BE NATURAL, BUT KEEPING THEM HAS BENEFITS

Due to hormone loss, we humans do not maintain perfect control over our functions permanently.

Kept healthy by our hormonal tools, we are fine up to age 25 or so, but thereafter we begin losing hormone production at a rate of about 1% per year, overall.

This produces a slowly accelerating decline in the efficiency of our metabolic management systems, which become “skewed” to a greater or lesser degree in one or another direction, depending on how our individual internal organs respond to reduced hormone levels.

In the opinion of Functional Medicine afficionados, our progressive loss of hormone production, though naturally occurring and 100% pervasive, is a disease and the resulting deviations from perfect health should be considered to be ill-effects of a pathological process.
From the Metabolic Medicine point of view, natural aging due to hormone loss is modifiable, if not truly treatable: hormonal balance is safely and easily acheived and with inexpensive, intuitive surveillance, can be perfectly timed.

Each individual, male of female, responds to hormonal loss with his or her own pattern of symptoms: depending on the individual organ’s sensitivity to lowered hormone availability there may be hair loss, weight gain, recurrent acne, dry skin, thin finger nails, allergies, high blood pressure, diabetes, autoimmune diseases, psychological change, cancer, neurological disease or other problems.
In addition stress, endemic to our modern lifestyle, can trigger suppression of thyroid function as an energy-saving reaction. When this happens all systems lose efficiency: muscles (including heart muscle) weaken and ache, the metabolic rate falls and we gain weight, loss of self-confidence leads to anxiety/depression and any pre-existing effects of hormonal reduction are accentuated.

While most people begin their disabilities at 26 (or earlier), many appear to be unaffected until much later. There is such a wide spectrum of “aging” effects that the majority are able to “carry on as usual” and the ones who fall by the wayside early in life are regarded as poor eaters, unhealthy due to bad habits or simply “unlucky”.
Nevertheless one thing is clear: no-one escapes the trap into which we are born and our “slide down the razorblade of life”, whether fast or slow, is inevitable.

As we age, most of the parameters by which our health professionals measure health remain stable and reasonably constant until some major system fails: tests for the function of the heart, blood vessels, kidneys, liver, lungs, intestines, endocrine glands, brain, bones etc remain sufficiently stable that hardly anyone shows obvious evidence of deterioration.

Unfortunately however errors are built into our surveillance plan:
[1] The hormonal balance, the measurable parameter which affects the function of all organs, changes steadily and can be monitored to give some indication of the general state of affairs, is ignored: decreasing test results are labeled “age-related” and considered “natural and normal for age”, thereby being relegated to the “interesting, but unimportant” file.
Let’s think about what we lose as aging progresses:
– Consider DHEA – it is precursor for Testosterone, Progesterone, Oestradiol, Cortisol and a host of microhormones which keep our parts working: all our cells, including thyroid cells, need it to maintain perfect function.
– Consider Testosterone: Zero “T” (normal 20-30 picomoles/Litre), often found in young women (I had a patient aged 23), is easily, safely treated with DHEA or “T” cream, but is usually ignored.
– Consider Progesterone: it rules the menstrual cycle, prevents PMDD, counteracts fatmaking Oestrogens and is raw material for Allopregnanolone (Q.V., Infra).
– Consider Allopregnanolone, darling of neuropsychiatry, which prevents and treats depression, ensures good sleep, is essential for memory, and maintains / repairs the brain. (12)
– Consider Oestradiol: it maintains the female “parts”, keeps the skin young and makes bones stronger.
…None of this is news, yet the progressive loss of all these hormones is accepted as “normal for age” and unremarkable: the ill-effects are accepted as inevitable and we are told to “live with it”!

[2] One hormonal system, the thyroid, is not tested accurately because TSH, which the pituitary gland sends out when it needs T4, is considered to be the only necessary thyroid test, although it only speaks for the pituitary’s need for T4 and has nothing to do with the body as a whole.
Consider the following:
– T3, your efficiency accelerator, is hardly ever measured and its “normal range” is unbelievably wide.
– Reverse T3, produced when the metabolic brake is applied and whole-body efficiency falls, is virtually never measured.
– Many anticancer drugs work by blocking T3, because cancer cells need it (all cells need T3).

[3] Mainstream doctors don’t test for vitamins and minerals, excepting Electrolytes, Vit B12, Iron, Calcium, Magnesium and Phosphorus. Although we know that an overload of Lead, Mercury and many other metals can be deleterious, tests for metal poisoning are almost never done and chelation treatment for metal overload is regarded as “quackery”.

WE CAN DETECT THE START OF HORMONE LOSS AND WE CAN REMEDY THE PROBLEM

A PLAN FOR HEALTHY AGING:

Age 5-15: Hormone information / awareness courses are taught in high school, to improve basic knowledge of the subject among the general population, facilitating the health practitioner’s surveillance and instruction of patients.

Age 15-25: A “wellness assessment questionnaire” and a short list of tests, most of which are inexpensive and easily available, are assessed by the family physician at age 15 and repeated every 5 years to age 25. thereafter or when as soon as symptoms of hormone loss begin.

Age 25-35: The wellness questionnaire and tests are repeated every 3 years.
The onset of symptoms, or an abnormal test result, triggers referral a brief explanation by the family doctor and referral to a health education professional (a well-paid paramedic, or nurse).
The the HEP reviews all aspects of hormonal balance, to ensure understanding of the diagnosis and proposed preventive therapy.

When the person concerned is ready to embark on (necessarily lifelong) hormone restoration and surveillance by testing, they themselves request a trial of therapy: this request is a mandatory prerequisite to prescription.
Refusal of advice or postponement of surveillance and/or therapy, is the individual’s prerogative, to be accepted without question by healthcare professionals, garnering no consequences.

FAQ

Q: WHAT’S THE POINT OF ALL THIS?
A: To reduce and delay body-system deterioration due to hormone deficiency. (1)

Q: WON’T IT BE EXPENSIVE?
A: It is a lot cheaper to prevent, than to cure. (2)

Q: HOW CAN WE AVOID OVERTREATMENT?
A: Repeated tests show the effect of therapy and the dose of hormone is adjusted accordingly.

Q: WHAT ABOUT HORMONE – DEPENDENT CANCER, LIKE HER-2 BREAST CANCER?
A: These cancers need the hormones to grow, but are not caused by the hormones.
A: Maintainance of DHEA, Melatonin, Progesterone etc deters cancer formation (4)

Q: PEOPLE WITH PCOS HAVE HIGH DHEA – WILL YOU CAUSE PCOS, BY INCREASING DHEA?
A: Not all have the high DHEA; it is caused by PCOS (not the other way around). (5)

Q: SUPPOSE TESTOSTERONE PRODUCES A PROSTATE CANCER?
A: That idea is wrong. Testosterone opposes Prostate Ca formation & low Testosterone aids it.
A: The Mayo Clinic still endorses the idea that P cancer should be treated by blocking T, (9), but
Testosterone prevents Prostate cancer and can be used as a treatment, in some cases. (6,7,8).

Q: DON’T HORMONES PREVENT PREGNANCY?
A: Only artificial hormones in birth control pills do, not hormones made by human glands. (10)

Q: AMD IS CAUSED BY THYROID HORMONE – CAN ThHormone MAKE YOU BLIND?
A: There is a link between higher levels of T4 and spontaneous AMD, not with Rx of T3 and T4. There must be some other factor that we have not as yet found: why would an essential hormone ruin vision? (11)

Q: WHAT ABOUT THYROID CANCER?
A: The story is the same as for other hormone-sensitive tumours: the cancer cells need thyroid hormone to grow,  but TH does not cause the cancer.

REFERENCES

For brevity, only a few are listed. Many more are available through NCBI.

(1) The “multiple hormone deficiency” theory of aging: is human senescence caused mainly by multiple hormone deficiencies? T Hertoghe 1 Ann N Y Acad Sci 2005 Dec;1057:448-65. doi: 10.1196/annals.1322.035. https://pubmed.ncbi.nlm.nih.gov/16399912/

(2) The Healthcare Imperative: Lowering Costs and Improving Outcomes: Workshop Series Summary (Book).

https://www.ncbi.nlm.nih.gov/books/NBK53914/

(4) Hormone-sensitive cancer: Wikipedia, the free encyclopedia, https://en.wikipedia.org/wiki/Hormone-sensitive_cancer

(5) Adrenal Androgen Excess and Body Mass Index in Polycystic Ovary Syndrome

Carlos Moran, Monica Arriaga, Fabian Arechavaleta-Velasco, Segundo Moran

The Journal of Clinical Endocrinology & Metabolism, Volume 100, Issue 3, 1 March 2015, Pages 942–950, https://doi.org/10.1210/jc.2014-2569 https://academic.oup.com/jcem/article/100/3/942/2839480

(6) Does Testosterone Cause Prostate Cancer? Stephanie Watson — Healthline, September 18, 2018

(7) Testosterone as a Drug, Johns Hopkins 05/01/2018 Dr Denmeade https://www.hopkinsmedicine.org/news/articles/testosterone-as-a-drug

(8) Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study Benjamin A Teply 1 , Hao Wang 2 , Brandon Luber 2 , Rana Sullivan 2 , Irina Rifkind 2 , Ashley Bruns 2 , Avery Spitz 2 , Morgan DeCarli 2 , Victoria Sinibaldi 2 , Caroline F Pratz 2 , Changxue Lu 3 , John L Silberstein 3 , Jun Luo 3 , Michael T Schweizer 4 , Charles G Drake 5 , Michael A Carducci 2 , Channing J Paller 2 , Emmanuel S Antonarakis 2 , Mario A Eisenberger 2 , Samuel R Denmeade 6 Clinical Trial, Lancet Oncol. 2018 Jan;19(1):76-86, doi: 10.1016/S1470-2045(17)30906-3. Epub 2017 Dec 14. https://pubmed.ncbi.nlm.nih.gov/29248236/
(9) Hormone therapy for prostate cancer is a treatment that stops the male hormone testosterone from being produced or reaching prostate cancer cells MAYO CLINIC, April 9, 2021 https://www.mayoclinic.org/tests-procedures/hormone-therapy-for-prostate-cancer/about/pac-20384737

(10) Birth Control Pills https://www.webmd.com/sex/birth-control/birth-control-pills

(11) Exploring the link between thyroid hormones and vision loss https://blogs.biomedcentral.com/on-medicine/2015/04/30/exploring-link-thyroid-hormones-vision-loss/

(12) Allopregnanolone, the Neuromodulator Turned Therapeutic Agent: Thank You, Next? Graziano Pinna*Department of Psychiatry, The Psychiatric Institute, University of Illinois at Chicago, Chicago, IL, United States. Front. Endocrinol., 14 May 2020 | https://doi.org/10.3389/fendo.2020.00236
https://www.frontiersin.org/articles/10.3389/fendo.2020.00236/full

THINK ABOUT “NORMAL”


Before we begin, please remember that I am not a professorial-level expert on this subject, so what I have to say here is merely my opinion, which I think is worth adding into the discussion of this complicated subject, but which, I must admit, cannot be the last word.

NORMAL

In health-related fields, “normal” is not a single number. It is a reference range or reference interval, against which a health professional can compare a urine, blood or other test result in order to decide whether it is, or is not, within “normal limits”.

Calculation of a “normal” curve is simple for a mathematician, but complicated for most of us, as you will gather from Figure 1:

” When we assume a normal distribution, the reference range is obtained by measuring the values in a reference group and subtracting a “standard deviation” on either side of the mean. This leaves the values found in ~ 95% of the test population.
The 95% interval can be estimated by assuming a normal distribution of the measured parameter, in which case it can be defined as the interval limited by 1.96[3] (often rounded up to 2) standard deviations from either side of the mean (the expected value).
Be that as it may, in the real world neither the population mean nor the population standard deviation are known.
They both need to be estimated from a sample, whose size can be designated n.
The population standard deviation is estimated by the sample standard deviation and the population mean is estimated by the sample mean (also called mean or arithmetic mean). To account for these estimations, the 95% prediction interval (95% PI) is calculated as: 95% PI = mean ± t0.975,n−1·√(n+1)/n·sd.

……… If that sounds suspiciously complicated, don’t look at me: ask your favourite math genius for his/her usual facile explanation!
……… Suffice it that the reference range encompasses results found in 95% of a reference group taken from a healthy population.
……… There are also optimal ranges (ranges that we think indicate optimal health) and ranges for particular conditions or situations (such as pregnancy reference ranges for hormone levels).
………. My preference is for optimal ranges and I have serious doubts about the accepted “normal” ranges of quite a few tests: see below.
.…….. Caveat: the blithe acceptance of the idea that 95% of a “healthy” population will have “normal” levels for all test results is overly optimistic. This assumption is contrary to doctors’ age-old principle of “a high index of suspicion” and must lead to underdiagnosis.
…….. Therefore Caveat: since our metabolic systems are interdependent and mutually, unpredictably variable in one way or another, the individual human should not be included in a population sample for estimation of “normal” values unless his/her results are within normal limits for all other available tests. Thus, eligiblity for an estimation of normal should be denied if the BMI is suspicious, if there is any diagnosable physiological/metabolic/genetic aberration, if the chronological age is < 20 or > 25 or if the psychological balance is suspect.

DON’T CONFUSE “NATURAL” WITH “NORMAL”

NATURAL NORMAL: Many systems change over time and the tendency of our “gurus” is to modify “normal” according to age.

Consider “natural normal” for DHEA (in micro-moles Litre), calculated as:

Age Female Male
Newborn4.5 – 104.5-10Mother gives her baby quite a lot
01-12 Yr< 5.0< 5.0We don’t make much DHEA as kids
13-29 Yr< 11< 11Just before puberty, production spikes *
30-39 Yr<7.3<14Femmes slow output at age 25
40-49 Yr<6.5<14Males usually keep it up through 45
50-59 Yr<5.4<8.4By 50, the ladies are in real trouble **
60-69 Yr<3.5<7.9By 65, the men are in the same boat **
70-79 Yr<2.4<4.7At 70, we are all over the hill
80-99 Yr?? 0.0?? 0.0At 80, only the brain makes DHEA **
* Probably, Melatonin pulls the trigger and DHEA causes the changes.
** I have observed that symptoms start when DHEA falls below 5.0 µMol/Litre, in both males and females.
*** Only the great apes, including us, make DHEA in the adrenals. The brain makes it for its own use and in lesser animals, is the only source of this all-important prohormone.

CLEARLY, THIS SCHEDULE TELLS US SEVERAL THINGS:

[1] males produce more DHEA than females.

[2] women begin to reduce production by age 25 and men, in their 40s.

[3] production is at infant levels or less by 60 and by 80, is close to zero.

[4] the researcher of the DHEA range didn’t know what the lower limits are.

[5] if DHEA is important, the human race has a problem.

[6] failing production is natural, but not normal, as we age.


Consider “natural normal” for Thyroid hormone (picoMoles/Litre).
In 2005 Leonard Wartofsky and Richard A Dickey wrote, (paraphrased) It has become clear that our reference ranges are no longer valid. We have more sensitive TSH tests and also, we now realise that previous reference populations included people with (low) thyroid dysfunction, whose high TSH levels led to a spuriously high reference range for TSH in the group. Recent laboratory guidelines from the National Academy of Clinical Biochemistry indicate that more than 95% of normal individuals have TSH levels below 2.5 mU/liter.

(2) In 2007 Martin I. Surks and Joseph G. Hollowell said as follows (paraphrased)……
The TSH median, 97.5 centile and prevalence of subclinical hypothyroidism (SCH) increase progressively with age. Age-adjusted reference ranges would include many people with TSH greater than 4.5 mIU/liter.
They continued: ”Without thyroid disease”, 10.6% of 20- to 29-yr-olds had TSH greater than 2.5 mIU/liter.” *
In the 80+ year-old group “without thyroid disease”, 14.5% had TSH greater than 4.5 mIU/liter.
TSH frequency distribution curves of the 80+ year-old group showed higher TSH.
The 97.5 centiles for the 20–29 and 80+ year-old groups were 3.56 and 7.49 mIU/litre, respectively.
70% of older patients with TSH greater than 4.5 mIU/liter were within their age-specific reference range (up to 7.49)**.

In spite of these findings (almost 100% of) our medical doctors preferred to think like Surks and Hollowell and the reference range for TSH has remained unchanged. ***
However to me, the implications are clear:
(A) Wartofsky and Dickey were correct and the upper limit of normal TSH should be 2.5, but they should have realised that 10.6% of their 20-29-year-olds were in fact, hypothyroid and should have excluded them. ****
(B) Surks and Hollowell would have done better to label the older folks hypothyroid, rather than concluding that “high TSH is normal for the older population”: what their findings mean to me is that a large percentage of the 80+-year-olds were hypothyroid and should have been exclude from their calculation of normal.
(C) “AGE-SPECIFIC NORMAL”, or “NATURAL NORMAL” makes no sense. “Normal” should be understood to mean the status of healthy humans aged 20-25 and an abnormal finding for any test should disqualify the candidate for all estimates of “normal”.

* This implies that 10.6% of the 20-29-year-olds were hypothyroid and should not have been included in a calculation of “normal”: .

** Any result >2.5 suggests hypothyroidism, so this implies that more than 14.5% of the 80+ – year olds were hypothyroid: including them in the “normal” group means that 15+% of 80-yr-olds won’t get the treatment they need !

*** I dare suggest that you should apply fair logic to every paper you read, so as to exclude glaring errors and prejudices such as these from your belief systems.

**** Think about it – if I am right, since the thyroid hormone dictates the efficiency level of every cell and system in the body, and if 10.6% (or more) of the thyroid test study population should have been excluded from the calculation of “normal” thyroid hormone levels, then the parameters for all our other tests could be wrong and maybe a lot of tests might be invalid !

MESSAGE

– Many other hormones suffer the same fate as DHEA: Melatonin, Progesterone, Allopregnanolone, Testosterone and Thyroid hormone all go down over time, mostly by slow, gradual loss of production.
– In some people several hormone levels can “crash” suddenly, causing various symptoms of deficiency depending on which hormones are involved. This can happen with Melatonin in the “teens”, Progesterone and Allopregnanolone in the twenties, Testosterone in the thirties or earlier and particularly Oestrogen, which disappears in the early fifties but can fall to zero in the late thirties or early forties.
– Thus assesssment of “normal” in the presence of “natural age related hormonal change” is very difficult.
– To give medical investigators their due, a concerted effort is always made to include only the fittest individuls in the group evaluated. However there are instances in which unknown or ignored factors lead to a “curve ball” situation and consequent unreliability of an accepted “normal” range.
– IN SUMMARY, aberrations of hormonal production are pervasive and the interdependence of hormonal systems is delicate: test subjects should be BETWEEN AGE 20 AND 25 YEARS and ALL THEIR OTHER RESULTS SHOULD BE 100% NORMAL, for inclusion in studies to calculate a “normal” reference range for whatever test is to be evaluated.

In the next section I will consider, as examples, TSH as a stand-alone test for thyroid function and DHEA as a marker of aging.

REFERENCES

(1) The evidence for a narrower thyrotropin reference range is compelling
Leonard Wartofsky 1 , Richard A Dickey, J Clin Endocrinol Metab, 2005 Sep; 90(9):5483-8 PMID: 16148345 DOI: 10.1210/jc.2005-0455 .https://pubmed.ncbi.nlm.nih.gov/16148345/

(2) Age-Specific Distribution of Serum Thyrotropin and Antithyroid Antibodies in the U.S. Population: Implications for the Prevalence of Subclinical Hypothyroidism:
Martin I. Surks, Joseph G. Hollowell, The Journal of Clinical Endocrinology & Metabolism, Volume 92, Issue 12, 1 December 2007, 4575–4582, https://doi.org/10.1210/jc.2007-1499 01 Dec. 2007.
https://academic.oup.com/jcem/article/92/12/4575/2596923?login=true

New Finasteride Lawsuit: Renewed Attention to Psychiatric, ED Adverse Event Reports


Medscape Medical News

Alicia Ault, September 23, 2021 https://www.medscape.com/viewarticle/959296?spon=15&uac=235227EV&impID=3672148&sso=true&faf=1&src=WNL_mdpls_210928_mscpedit_urol

University of the West Indies ranks in the top 1.5% world wide !!!


UNiVERSITY OF THE WEST INDIES COAT OF ARMS

A classmate just sent me this letter from our Vice-Chancellor:

“It is with humility and a profound sense of pride and gratitude that I am able to share with you the very good news that our university has finally reached the top. This is the finding of the Times Higher Education (THE) World University Rankings.

The 2022 ranking results, officially released on September 2, show that The UWI soared above prior years’ results. This excellent outcome is achieved despite the budgetary challenges associated with the growing fiscal problems of our contributing governments, the financial difficulties of our private sector, and the aggravation caused by the impact of the COVID-19 pandemic.

The ranking result shows that The UWI, from a global field of some 30,000 universities and top class research institutes, now ranks in the top 1.5% of the world’s best. This is an historic achievement and worthy of celebration. We have every reason to join with our global colleagues in marking this Caribbean journey to the top of the university world.

We must celebrate the visionary leadership and contribution of earlier colleagues on whose strong and dependable shoulders we stand today. I offer unlimited respect to you—the inspirational, irrepressible UWI community. We thank our governments especially, who have empowered their UWI through the good and bad times. Thanks to them, we are an excellent global university rooted in the Caribbean.

Despite COVID-19 and related challenges and disasters, the university’s management did not flinch nor did we retreat from our commitment to lead this university through whatever turbulence surrounded us. With your solidarity, we stood up to face the headwinds emanating from multiple quarters; we represented the culture of resilience embedded in our history, and we summoned our collective energy to propel us to this coveted place.

Congratulations UWI! We are at 1.5 and we are very much alive! Let us be even more focused and resolute as we enter this new academic year.

I take this opportunity to give thanks for the grace we have experienced while offering condolences and solidarity with each and every one of you who suffered loss and is experiencing illness.

This year we have declared to be the onset of the ‘Revenue Revolution’ in which we convert our top ranking global reputation into sustainable revenue. This is our core project for the foreseeable future. We will achieve this target. Yes we will.

Blessings!

Professor Sir Hilary Beckles: Vice-Chancellor

Hormone therapy does not cause dementia


https://medicalxpress.com/news/2021-09-menopausal-hormone-therapy-linked-dementia.html

I am publishing this link because the headline sounds interesting and will pique your interest, but in fact the article as written is only in regard to “Menopausal hormone therapy” and nothing to do with the multi-hormonal support provided by Bioidentical HRT as you and I know it.

With a headline reading “Menopausal hormone therapy not linked to increased risk of developing dementia”, the British Medical Journal avers that treatment with “estrogen and progestagen” does not cause dementia. However since it goes on to explain their view that “The primary indication for hormone therapy continues to be the treatment of vasomotor symptoms, and the current study should provide reassurance for women and their providers when treatment is prescribed for that reason”, ** it is evident that the body of the article has no bearing on detailed hormone balancing programs, in which all deficient systems are supported.

It is clear that the writer is not familiar with the reasons for HRT, that “Menopausal hormone therapy” is quite different from Bioidentical HRT and that the other ruminations in the article, particularly with respect to Alzheimer’s disease, are not robust. So while the conclusions drawn may be correct for a patient population receiving “Menopausal hormone therapy”, said conclusions should not be applied to persons treated correctly in a full, complete and closely supervised BIHRT program.

** Vasomotor symptoms do provide a trigger which indicates that the time has come to examine the hormonal balance and initiate BIHRT. However the object of BIHRT, as you will agree, is not just to stop the symptoms, but to prevent the complications, of menopause: the list includes osteoporosis with “fragility fractures”, weight gain (therefore diabetes, hypertension, etc.), psychological disturbance including anxiety, irritablilty and depression, hair loss, skin changes, insomnia, functional hypothyroidism and and the rest of the downside of menopause. The vasomotor symptoms do go away with treatment, which is the patient’s primary concern, but ** the HRT professional does not treat complaints. A BIHRT Rx is written to ensure health, preserve life and maintain lifestyle. It is not solely “treatment” for the symptoms of menopause.

TREAT ALZHEIMER’S for US$65,000 per YEAR ? OR, WHAT CAN YOU ACTUALLY DO ?


On June 7th, 2021, the American Food and Drug Administration (FDA) “conditionally” approved Aducanumab (Aduhelm), an amyloid beta-directed monoclonal antibody which treats Alzheimer’s disease by removing BetaAmyloid from the brain. Aducanumab is the first new Alzheimer’s drug since 2003, and the first potentially disease-modifying agent.

The approval is surprising, because: (1) Of (only) two trials, one showed no benefit from the drug. (2) One third of drug recipients developed brain swelling and other side effects. (3) Only 9% of patients’ Alzheimer’s improved. (4) The cost of treatment is US$56,000 per year and the drug does not produce a cure, because it only removes Amyloid present in the brain – it does not prevent production of more amyloid. (5) Several previous Amyloid-removing drugs had no beneficial effect on Alzheimers patients.

SO MAYBE THE BEST SUGGESTION IS, LOOK AFTER YOURSELF. Don’t wait for a diagnosis of Alzheimer’s disease, because by the time it’s diagnosed, half of your brain power is gone and cannot be rebuilt. Instead, reduce your chances of devleoping Alzheimer’s by attention to and maintenance of your hormone balance.

The point here is that while we do not have proof that optimal hormone balance reduces our liability to Alzheimer’s, balancing does no harm, provides many benefits and should be done anyway.

WITH THIS IN MIND, HERE ARE SOME SUGGESTIONS FOR PRE-ALZHEIMER’S SUBJECTS:

In managing ageing generally and for Alzheimer’s prevention in particular, try to ensure that the hormonal milieu in which your body functions is optimal for cell maintenance and efficiency. (1) If your hormones are unbalanced, the nutrients you take will not work as well, so the first thing to do is to “balance” your hormones: first the “neurosteroid” hormones, which provide a “level base” for all the cells in your body and then thyroid hormone (“T3”), which is necessary for the efficient function of every cell. (2) Supply your body with the vitamins, “essential” amino acids and minerals which it needs to run itself as it should. (3) Read ‘the end of Alzheimer’s, by Dr. Dale Bredesen.

REGARDING DIETARY SUPPLEMENTS, SEE THE LIST BELOW: ITEMS MARKED WITH ** ARE ADVISED FOR EVERYONE AND THOSE MARKED WITH * ARE IMPORTANT. Unmarked items are reliably present in food, or only helpful for various conditions/diagnoses. Discuss this with a pharmacist or health food store: ask for products with combinations of nutrients. NOTE THAT THIS IS A HUGE LIST, OF WHICH YOU MAY NEED ONLY A SELECTION. DISCUSS IT WITH A FUNCTIONAL MEDICINE, NATUROPATHIC, OR HERBALIST PROFESSIONAL.

ESSENTIAL AMINO ACIDS AND MINERALS: Acetyl L-carnitine**, 500 mg …….. works with CoQ10, maintains mitochondria, heart, muscles, brain and nerves. Chromium Picolinate*, 25 µg ……… if your diet includes cruciferous vegetables, you probably don’t need chromium. Citicholine*, 250 mg twice daily ….. Helps the brain, assists the adrenals. Do not take if you have PCOS or diabetes. CoQ 10**, or Ubiquinol, 200 mg …. Supports mitochondria. Destroyed by statins. A “must” for those taking statins. Magnesium Threonate**, 200 – 400 mg, or sufficient to relieve constipation without producing loose stool. Melatonin**, 1–10 (? 20) mg, as tolerated ……… available as drops, tablets. Sublingual is probably best ………… Melatonin is the second most important antioxidant: look it up !! Methyl Tetrahydrofolate (MTHF, Vitamin B9)** 1 – 5 mg …………… do not take “folic acid”. NAC (N-acetylcysteine), 600 – 1800 mg** ……… replenishes glutathione, the most important antioxidant. Nicotinamide riboside (Vitamin B3)**, 100 mg ….. Anti-inflammatory, facilitates exercise, helps heart and kidneys. Omega-3*, 1 g ….. A healthy diet includes sufficient omega-3, but if “brain building”, take 1–2 g. Pyrroloquinoline quinone, (“PQQ”) 20 mg** supports, stimulates and regenerates mitochondria, helps cognition. Resveratrol**, 100 mg: ………… drinking red wine does not provide sufficient resveratrol. Selenium, 200 – 400 µg, for normal thyroid function and to prevent/treat autoimmune diseases. Trimethyl glycine (betaine)*, 500 mg twice daily…. produces SAMe. Anti-inflammatory, anti-homocysteine. Zinc**, 40 mg: do not add copper, unless instructed to do so by your HC provider.

VITAMINS: Some combination of the following (most of these are present in a normal diet, so if you are healthy and eat well, there is no need to adhere closely to the dosages noted below).

Vitamin B complex: take a VBCo pill once or twice daily. Vitamin B preparations, made by many different manufacturers, are more or less equal: pick one based on how closely its ingredients match the list below: Vitamin B1* (Thiamine), 50 mg…… Vitamin B2*(Riboflavin ):…… from many foods – supplementation is not usually necessary. Vitamin B5 (Pantothenic acid)* 100 mg ; from foods – supplementation not usually necessary. Vitamin B6*: Optimal blood level 60-100 nmol/L. Rx P5P (Pyridoxal 5 Phosphate), 2 mg ……. too much B6 is toxic. Vitamin B12: Normal blood level =138-652. Optimal = >650…….Rx methylcobalamin/Adenosyl Cobalamin 1 mg. Most of us don’t need it. Vitamin C**, 2–3 g (Linus Pauling used to recommend 9 g per day). Vitamin D3**, 3000+ iu: ask for a test – take enough to produce a blood level of 100-200 nmol/L.Vitamin E, 800 units ……… not more; in large amounts, or in combination with anticlotting agents, Vit. E slows blood clotting. Vitamin K2**, 100 mg…………… this must be “K2”, specifically.

BOTANICALS (discuss with your Naturopath, Herbalist or health food person: Curcumin, 500 mg daily. Ashwaghanda, 500 mg twice daily (reduces amyloid). Bacopa Monieri, 250 mg, twice daily (improves cholinergic neurotransmitter systems). Gotu kola, 500 mg twice daily (improves alertness). Lion’s mane, 500 mg (increases nerve growth factor). Rhodiola, 200 mg (antianxiety). Shankhpushpi (“skullcap”), 2 caps (enhances branching of neurons). Guggul, 300 mg with meals (absorbs toxins in the bowel). Black cumin:? Dosage (antiallergic, immune booster, antioxidant, ? Bactericidal for H. pylori).

I need help with a minor concern


This website is a free medical information source for my old patients and anyone who needs info about hormones.

I don’t want to put annoying, indiscriminate ads on the site, I have nothing to sell and I don’t want to ask for a subscription.

Perhaps I could run ads for helpful things which I consider worthwhile, like vitamins, essential minerals, healthcare appliances etc, but I don’t know the best way to approach manufacturers [so that I get a fair fee for allowing the ads onto my site].

If any of you can offer advice on this subject, please join up and enter it in the blog.

G. A. Harry.

POST-FINASTERIDE SYNDROME


This note is in response to a query regarding PFS (the post-finasteride syndrome) from Dr. Philip Roberts, the patient-support director of the post-finasteride syndrome foundation.
It is offered gratis and in humanitarian interest, as my personal opinion. It is based to some extent on my previous knowledge and experience and bolstered by current information available on the www.
Please bear in mind that I am to be regarded as a well-informed layman: I am not an academic, a recognised expert on functional medicine or any sort of pundit and now post-retirement, I am no longer a registered physician. Therefore my musings amount to speculative suggestion only and should not be construed as instruction or advice to Dr. Roberts, or to PFS sufferers.

DEFINITION / BACKGROUND

Finasteride was patented in 1984 and approved for medical use in 1992. It is available as a generic.
Sold as Proscar, Propecia and other brand names, it was initially used to treat benign prostatic hyperplasia and subsequently hair loss, in men. It can also be used to reduce hair growth in women and as a part of hormone therapy for transgendered females. In 2018, it was the 87th most common medication in the United States, with over 8.9M prescriptions.
Adverse effects from finasteride are said to be rare, however some men experience sexual dysfunction, depression, breast enlargement and or a host of other symptoms, which may persist after stopping the medication (Finasteride may also hide the early symptoms of prostate cancer).
Clinical studies have revealed both high efficacy of treatment and a favorable safety profile, establishing the drug as first-line treatment for male pattern hair loss.
In 2012, Sato and Takeda [1] reported on efficacy and safety of 1 mg oral finasteride for treatment of male pattern hair loss in a very large population study (3,177 Japanese men). 87.1% reported increased hair: 11.1% “greatly”, 36.5% “moderately”, and 39.5% “slightly” increased. Further, the response rate improved with increasing duration of treatment and only 0.7% reported adverse reactions.

THE POST-FINASTERIDE SYNDROME:

PFS has been reported in men who have taken oral finasteride, for either hair loss or BPH. [2,3]
Reported symptoms, including depression, cognitive impairment, loss of libido, erectile dysfunction, reduction in penis size, penile curvature or reduced sensation, gynecomastia, muscle atrophy and severely dry skin, continue despite quitting finasteride. [4] The condition allegedly may have a life-altering impact on sufferers and their families, such as job loss, the break-up of romantic relationships or marriages and suicides.

The Post-Finasteride Syndrome Foundation (www.pfsfoundation.org), a nonprofit organization, is dedicated to helping fund research on the characterization, underlying biologic mechanisms, and treatments of PFS and to improving public awareness of the condition.

The obstacles to finding a solution to the vexing situation in which sufferers find themselves is personified in two online articles, which I have dubbed “A DERMATOLOGIST’S VIEW” [5], paraphrased below and “A Comment on the Post-Finasteride Syndrome” [6], both from Dr Ralph Michel Trüeb, et al.

A DERMATOLOGIST’S VIEW (I have paraphrased this article, in the interest of space).
“Finasteride represented a breakthrough, with high efficacy and safety.
PFS, characterized by sexual dysfunction, somatic symptoms, and psychological disorders, has been claimed to occur in men who have taken oral finasteride. In our opinion, PFS is a “mystery syndrome” like amalgam illness, chemical sensitivity, Morgellons disease, and Koro (fear of the genitals shrinking and retracting into the body): symptoms cannot be explained biologically and frequency of consultation parallels media coverage, indicating suggestibility. Finally, patients hold to their belief system despite rational argument, indicating a delusional aspect to their disorder. We report our first case, with evidence that PFS is delusional, due to histrionic personality. In case of adverse effects, finasteride or dutasteride treatment should be stopped.
Patients are unlikely to benefit from any androgen and attention must focus on treatment of psychopathological disorders and sexual symptoms, with psychotherapy and psychotropic agents depending on the underlying depressive, delusional, or somatoform disorder”.

CONSTRUCTIVE ANALYSIS:
Finasteride is a 5α-reductase inhibitor and therefore an antiandrogen.
By blocking 5α-reductase, it reduces production of DHT (Di-HydroTestosterone) in the prostate and the scalp by about 70%.
Since 5α-reductase is the active enzyme in the synthesis of several anticonvulsant neurosteroids, including allopregnanolone, androstanediol and THDOC, finasteride also inhibits production of those essential hormones. **
Allopregnanolone, androstanediol and THDOC deficiency leads to depression, followed by functional hypothyroidism.
A PTSD/CFS/ME scenario is thus engendered, with devastating depression, subjective helplessness and suicidal ideation.

So let’s think about Allopregnanolone, Androstenediol and THDOC:

ALLOPREGNANOLONE is an antidepressant, anxiolytic, pro-social, anti-anger, pro-libido, soporific and pro-cognitive hormone made in the brain as well as in the adrenal glands.
It is responsible for brain maintenance and repair, including myelin sheath maintenance, nerve connectivity, nurture of new brain cells and memory.
It is mood-enhancing.
It generates endorphins and is anticonvulsive.
It relieves postpartum depression.
Deficiency of Allopregnanolone causes PMDD (PMS) (8), anxiety states, panic attacks and depression. Fluctuations in its blood level plays an important role in the pathophysiology of mood disorders, catamenial epilepsy, MS, Parkinson’s, Alzheimer’s and various other neuropsychiatric conditions.

ANDROSTENEDIOL is an intermediate in Testosterone synthesis from DHEA, so a reduction of its availability will reduce Testosterone levels.
This is not be a major problem for many, but in those who are already “Testosteropenic”, it often leads to a loss of self-confidence (therefore increased anxiety), reduced muscle maintenance, increased fat storage and perhaps an increased tendency to gynecomastia (which some males already have).

THDOC (deoxycorticosterone), is a potent positive allosteric modulator of the GABAA receptor, has sedative, anxiolytic and anticonvulsant effects. Changes in the normal levels of this steroid may be involved in some types of epilepsy (catamenial epilepsy), PMS, stress, anxiety and depression.
As with Allopregnanolone, reducing production of THDOC increases any tendency to anxiety and depression in the short term: time will tell whether long-term effects will be observed.

MY OPINION, IN VERY BRIEF

  • Reported effects in affected persons is horrendous and although PFS is rare (relative risk 1.66), it warrants careful analysis and thoughtful consideration.
  • Clearly, since the mechanism of action of Finasteride is to inhibit 5α-reductase, which transmutes Progesterone to Allopregnanolone, DOC to THDOC and DHEA to Androstenediol, prescription of Finasteride carries the risk of deficiency of all three Hormones.
  • Downregulation of Allopregnanolone lowers mood and reduces self-satisfaction and sense of tranquillity, setting the stage for anxiety and depression. Anxiety and depression are interpreted by the brain as stress and the stress results in cortisol output, which encourages preferential conversion of T4 into rT3. In this scenario Allopregnanolone deficiency produces mood swings and depression, the depression causes anxiety, the anxiety is interpreted by the brain as stress, the brain calls for a stress response, the tissues respond by converting T4 into rT3 instead of actve T3 and a hypothyroid state ensues.
  • Therefore PFS is due to idiosyncratic sensitivity to the neurodebilitating effects of ALLOPREGNANOLONE, THDOC, Androstenedione (and possibly other neurosteroid) deficiency, compounded by deep functional hypothyroidism (akin to PTSD and CFS) which serves to increase the anxiety and further suppress Allopregnanolone.
  • Regarding non-sexual symptoms of PFS: dry skin, hair loss, muscle aches, adiposity, skewing of the cholesterol balance, reduced cognition, chronic fatigue symptoms, low libido and anxiety with panic attacks are all symptoms of hypothyroidism .
  • Impotence can also be a low-T3 effect, as can peripheral neuropathy, pretibial oedema, constipation and innumerable other symptoms.
  • NOTES:
    (1) regarding DHEA: DHEA production falls 1% per annum from age 25 in all humans and is therefore deficient by age 30. It should be recommended as a supplement, for all.
    (2) Progesterone supplementation, at 50mg HS, improves sleep, memory, mood and self-satisfaction in males.
    (3) Penile curvature (Peyronie’s disease) must be a coincidental development unrelated to the other PFS effects.

INVESTIGATION

Investigation should include, in addition to routine studies, free Testosterone, IGF, DHEA, Oestradiol, Progesterone, fasting Homocysteine, HSCRP, TSH, free T4 & T3, rT3.

MANAGEMENT

[1] Contact a Metabolic Medicine or Functional Medicine MD, for an opinion re PFS.
[2] Correct Allopregnenolone deficiency with Pregnenolone and Progesterone, at bedtime.
[3] Supply (HS) Melatonin as an adjunct to Allopregnenolone, to improve sleep, mood and anxiety. [4] Supply DHEA (no more than 50mg /day, to avoid aromatisation to Oestrogen: >50mg may raise Oestrogen to female levels, producing gynecomastia and occasionally, painful breast cysts).
[5] Correct the functional hypothyroidism with Triiodothyronine (AKA Liothyronine), titrated up from 10mcg daily in 5mcg increments, to achieve a T3 level between 5.0 and 6.0 Picomoles/Litre. Do not try desiccated thyroid, because 70% of D.T. is T4. The T4 will not raise the serum T3: it will be processed preferentially to rT3. DO NOT PRESCRIBE Eltroxin or Synthroid, for the same reason.
[6] Test for HS CRP, Homcysteine, IGF, Heavy Metals and other markers as seems necessary and treat ad hoc.
[7] Test for T3 weekly, at 4 hours post-dose (Ideal dose time 4AM): because T3’s half-life is only 2-3 hours, there is no need to wait six weeks for re-estimation, as is done for T4, whose half-life is 5 – 7 days.
[8] Titrate Triiodothyronine dose to acheive a Free T3 of between 5.0 and 6.2 Picomoles/Litre. [9] Re-test for rT3 and other parameters later, when the serum T3 is > 5.0 Pm/L. [10] Recommend Vit D, B12, MTHF, NAC, CoQ10, I3C, Zinc, Iron, Magnesium, Selenium, Iodine etc, as necessary.
[11] Prescribe Zuranolone, when it becomes available, as a short-term adjunct to relieve symptoms: do not depend on Zuranolone to supplant the entire protocol because it will not eliminate the underlying cause of the syndrome

SIDE EFFECTS OF T3 OVERDOSE:
The classical side effects of T3 overdose are fast heartbeat, anxiety, hyper-reactivity/anger and “antsyness”, but they usually occur due to spiking of T3 when Cytomel is prescribed.
They are rare when slow-release T3 is taken and do not occur if the dose is titrated slowly to a maximum FT3 of 6.2 Pm/L.
The main effect of mild overdose, with T3 over 6.2 (optimal is 5-6), is feeling “high” ….. a feeling of being “on top of the world”, sharp and optimistic, with sharpened, bright colour vision, enhanced reds and greens and heightened perception.
The main symptom of insufficient dose is afternoon fatigue, with recurrence of hypothyroidism symptoms late in the day.

PROGNOSIS and FOLLOW-UP

I cannot estimate a time-frame for improvement in the patient’s symptoms, but the response to DHEA and Progesterone is usually rapid. Time to improvement in functional hypothyroidism will depend on the patient’s requirement for T3. Follow-up will depend on the subject’s condition, so the time-frame should be discussed between practitioner and patient.

Please note that the bottom-line idea is that PFS, should respond well to treatment with: 
DHEA [low dose: 50mg] for general support and Testosterone enhancement.
PROGESTERONE [low dose – 50-100 mg HS] for Allopregnanolone support and
Triiodothyronine, to eliminate Hypothyroidism [T4 makes functional hypothyroidism subjects, male or female, really sick].
PLEASE NOTE THAT I DO NOT PROMISE  A GUARANTEED CURE.

REFERENCES

[1] LONG-TERM (10-YEAR) EFFCACY OF FINASTERIDE IN 523 JAPANESE MEN WITH ANDROGENETIC ALOPECIA, Masayuki Yanagisawa1-3, Hiroshi Fujimaki2,4, Akira Takeda1,2, Mitsuru Nemoto1, Takayuki Sugimoto1 and Akio Sato: January 2019 DOI:10.15761/CRT.1000273, https://www.researchgate.net/publication/337105943_Long-term_10-year_efficacy_of_finasteride_in_523_Japanese_men_with_androgenetic_alopecia

[2] Meta-Analysis: Adverse Sexual Effects of Treatment with Finasteride or Dutasteride for Male Androgenetic Alopecia: A Systematic Review and Meta-analysis
Solam Lee 1, Young Bin Lee, Sung Jay Choe, Won-Soo Lee https://pubmed.ncbi.nlm.nih.gov/30206635/

[3] Meta-analysis: Effect of 5α-Reductase Inhibitors on Sexual Function: A Meta-Analysis and Systematic Review of Randomized Controlled Trials, Luhao Liu  1 , Shankun Zhao  1 , Futian Li  1 , Ermao Li  1 , Ran Kang  1 , Lianmin Luo  1 , Jintai Luo  1 , Shawpong Wan  1 , Zhigang Zhao  2: PMID: 27475241 DOI: 10.1016/j.jsxm.2016.07.006 From 493 articles, 17 trials / 17,494 patients were included. 9 trials evaluated 5ARIs in BPH. 8 trials reported 5ARIs in AGA. We included 10 trials (6,779 patients) on Finasteride, 4 trials (6,222 patients) on Dutasteride, and 3 (4,493 patients) on finasteride and dutasteride for AGA.
The relative risks for sexual dysfunction were 2.56 (95% CI = 1.48-4.42) in BPH and 1.21 (95% CI = 0.85-1.72) in AGA; those for erectile dysfunction were 1.55 (95% CI = 1.14-2.12) in BPH and 0.66 (95% CI = 0.20-2.25) in AGA and those for decreased libido were 1.69 (95% CI = 1.03-2.79) in BPH and 1.16 (95% CI = 0.50-2.72) in AGA. Conclusion: 5ARIs were associated with increased adverse effects on sexual function in BPH compared with placebo. However, the association was not statistically significant in men with AGA.

[4] Observational evaluation of 79 young men with adverse effects after finasteride: G Chiriacò  1 , S Cauci  2 , G Mazzon  1 , C Trombetta  1, PMID: 26763726 DOI: 10.1111/andr.12147 https://pubmed.ncbi.nlm.nih.gov/26763726/ Of 79 participants, 40.5% declared erection difficult, and 3.8% never achieved. Orgasm was difficult in 16.5%, and never achieved by 2.5%. 75.9%) had anhedonia, 72.2% lacked mental concentration and 51.9% loss of muscle tone/mass. Most frequent sexual symptoms were low penis sensitivity (87.3%), low ejaculation force (82.3%), and cold penis (78.5%).

[5] https://www.karger.com/Article/Fulltext/497362 Post-Finasteride Syndrome: An Induced Delusional Disorder with the Potential of a Mass Psychogenic Illness? Trüeb R.M.a · Régnier A.a · Dutra Rezende H.a · Gavazzoni Dias M.F.R.b

[6] A Comment on the Post-Finasteride Syndrome, Int J Trichology. 2018 Nov-Dec; 10(6): 255–261.doi: 10.4103/ijt.ijt_61_18, PMCID: PMC6369643 PMID: 30783332Hudson Dutra Rezende, Maria Fernanda Reis Gavazzoni Dias,1 and Ralph Michel Trüeb https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369643/

[7] Neuroprotective and Antiapoptotic Effects of Allopregnanolone and Curcumin on Arsenic-Induced Toxicity in SH-SY5Y Dopaminergic Human Neuroblastoma Cells, Neurophysiology volume 52, pages 124–133 (2020): H. Khodadadi, G. P. Jahromi, G. Zaeinalifard, M. Fasihi-Ramandi, M. Esmaeili & A. Shahriary https://link.springer.com/article/10.1007/s11062-020-09861-6

[8] Adrenal response to adrenocorticotropic hormone stimulation in patients with premenstrual syndrome: Gynecol Endocrinol. 2004 Feb;18(2):79-87, Lombardi I1, Luisi S, Quirici B, Monteleone P, Bernardi F, Liut M, Casarosa E, Palumbo M, Petraglia F, Genazzani AR. PMID: 15195499, DOI: 10.1080/09513590310001652955, https://www.researchgate.netpublication223979283_ACTH_and_Cortisol_Response_to_DexCRH_Testing_in_Women_with_and_without_Premenstrual_Dysphoria_during_GnRH_Agonist-induced_Hypogonadism_and_Ovarian_Steroid_Replacement