MedTech Investor: Check Out the Assumptions of Our Minimum Viable Product Scenario

In the present post, we present the bioZhena Business Assumptions. This is to draw attention to the big picture that emerges even in the Minimum Viable Scenario (MVS), the detailed assumptions of which have been worked from bottom up (with due attention to the TAM, SAM and the SOM). bioZhena Corporation’s goal is to implement the Full Value Scenario that was constructed based on the MVS. More on this in the closing paragraph of this post.

Now it’s the latter I am reaching out to. And I refer to Home Page of bioZhena’s Weblog to be reviewed in connection with the business assumptions. (Or Reproductive Health IQ Does Matter, a LinkedIn post.)

Here is a summary of the MVS, the Minimum Viable Product Scenario:

SUMMARY OF MINIMUM VIABLE SCENARIO’S SERVICEABLE AVAILABLE MARKET IN THE U.S. ALONE

US Trying-To-Conceive (TTC) Serviceable Available Market $$ at the TTC mean cost of $2,600 p.a. is $21,320,000,000

US Trying-To-Conceive Serviceable Available Market $$ at the TTC minimum cost of $200 p.a. is $1,640,000,000

US Initial Off-Label Birth Control Serviceable Available Market (SAM) $$ is $82,492,000

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Projection: FIRST PRODUCT SALES IN MONTH 16 POST FUNDING (first product application already FDA-cleared)

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Summary Comparison of Minimum Viable Scenario (MVS) with Full Value Scenario (FVS)

Click on the image for better legibility

(the URL is: https://biozhena.files.wordpress.com/2016/09/comparison-mvs-cf-fvs.pps )

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And now for the assumptions – with pictorial embellishments for dividers between the market segments.

Listing sources of market data (with some comments) followed by the resulting numerical USD market size assumptions.

‘Satyre et Bacchante’ by Jean-Jacques Pradier, marble, Palais des Beaux-Arts, Lille.

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Birth Control (BC) Market

CDC 2014 survey: 61.7% of the 60.9 million US women ages 15-49 practice contraception (= 37.6 million contraceptors), and of these 48.1% use the most common methods (the pill, sterilization, condoms, and long-acting reversible contraceptives). That leaves 38.3% or 23.32 million non-contracepting women.

un.org Trends in Contraceptive Use Worldwide 2015 Report, Annex Table II: Number of US married or in-union women using contraception = 28,600,000. Number of US women who have an unmet need for family planning = 2,560,000. Worldwide number of women using contraception is 758,000,000 and the number of women who have an unmet need for family planning is 142,000,000 (these are median data as of 2015). Couples often desire to control not just the number of children, but also the timing. We address this desire or need by design.

Next, per Guttmacher Institute 2016 fact sheet, nearly half (45% or 2.8 million) of the 6.1 million pregnancies in the U.S. were unintended in 2011 (and 42% of those ended in abortion). Contraceptive failure rate plays a big role in this. Meaning that, for 2.8 million of the 37.6 million contracepting women, their method fails (and they seek a solution). 43 million US women were at risk of unintended pregnancy in 2008. (Public expenditures on unintended pregnancies nationwide were estimated to be $21.0 billion in 2010.)

For this Minimum Value Scenario, the conservative assessment of the number of US women in the birth control market is to choose between the 43 million at risk in 2008 and the 2.8 million of unintended pregnancies in 2011 plus the 2,560,000 who have an unmet need for family planning. We choose the latter, which is much smaller, i.e. 2,800,000 plus 2,560,000 = 5,360,000 as the number of US women in the family planning (BC) market segment for our Serviceable Available Market. This is an indisputably conservative assessment of our Serviceable Obtainable Market in the birth control (BC) market segment in the U.S.

US costs of personal birth control average $1,006/year (Health Aff (Millwood) 2015 and americanprogress.org 2012). Since average ACA saving was 20%, then 100% = $ 251.5 times 5 = $ 1,257.50.  So, $ 1,257.5 – $ 251.50 = $1,006. (ACA = Affordable Care Act.) Double-check the reasonableness via this tweet.

Hence Our Birth Control (BC) Numerical Assumptions For the Minimum Value Scenario Are:

Number of US Women in the family planning (BC) market is 5,360,000

US Serviceable Available Market (SAM) $$ is $5,392,160,000

Worldwide Number of Women in the family planning (BC) market is 758,000,000

Worldwide Total Available Market $$ is very large even with only the unmet-need number of 142,000,000 women

E.g. if the estimate is based on the above US cost average, TAM is $142,852,000,000

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Initial Off-Label BC Market Upon the Ovulona Launch Assumed At 1%

Commercial market research compendium reports: The Trying-To-Conceive (TTC) tests are utilized for the unauthorized off-label use of aiding women’s natural birth control practice.

Quote: “About Half Who Use Tests Do Not Want Pregnancy”.

(http://www.marketresearch.com/Packaged-Facts-v768/Home-Medical-Tests-143386/).

Here we assume only 1% of the 8,200,000 US Fertility-Impaired Women Ages 15-44 (see below the CDC data on the TTC market), which is 82,000 women, translating at the assumed mean annual BC cost of $1,006 into an off-label $82,492,000 SAM upon the Ovulona launch into the TTC Market. To reiterate, we assume that 1% of those in the market for a tech tool aiding conception are in fact in the market to help themselves to avoid pregnancy by fertility awareness and will be off-label Ovulona users as soon as the Ovulona becomes available in the marketplace.

This is a reasonable conservative assumption in view of the 69.5 million US Catholics (the largest religious body in the United States) comprising 22% of the population^[1] as of 2015. The assumed 82,000 women represent a mere 0.1% of the Catholic population. See an example of unsolicited expression of interest in the Ovulona from a US Catholic. Ovulona market research with 5,000 US women revealed that 70% of those who would buy the Ovulona would switch from their present contraception method.

The assumed SAM [Serviceable Available Market] number of $82,492,000  represents 30.5% (but read on) of the annual retail sales of ovulation prediction kits (OPKs or LH kits) in the U.S. as they were reported in 2008/2009 when OPKs outpaced the annual sales of home pregnancy tests. The NYT article at http://www.nytimes.com/2009/04/02/business/media/02adco.html?_r=2 cited the annual OPK sales data of $270 million from IRI (Information Resources, Inc.). They derived it from in-store scanners at the retailer level for all of their major CPG clients (Consumer Packaged Goods companies) except for Wal-Mart. This info courtesy of Edward Saettone (via Linkedin Answers).

At annual growth rate of over 10% for personalized diagnostic tools (per PricewaterhouseCoopers), this suggests a SAM over $560,000,000 in 2016, and the assumed off-label SAM of $82,492,000 then represents ~15% of this documented and extrapolated figure for annual sales of OPKs in 2016. The SAM percentage (~15%) will be further reduced by the sales of the electronic ovulation predictor tests that have entered the market in the last decade or so.

For the worldwide assumption we take as base 6% of the worldwide number (758,000,000) minus the number in least developed countries (60,800,000) because: 1.  Only 6 per cent of married or in-union women worldwide used rhythm or withdrawal in 2015 (per un.org …/trendsContraceptiveUse2015Report.pdf), and 2. it is well known that especially this sub-population of women (and men) keep looking for a better tool to help them practice fertility awareness/natural family planning.  6% of 697,200,000 = 41,832,000.

Hence Our Numerical Assumptions For Off-Label Use In the Minimum Value Scenario Are:

Number of US Women off-label users upon device launch into the TTC Market segment (below) is 82,000

US Off-Label Serviceable Available Market $$ is $82,492,000

Worldwide Number of Women off-label users upon device launch is 41,832,000

Worldwide Total Available Market $$ is very large

E.g. if the estimate were based on the above US cost average, TAM is $42,082,992,000

 

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Trying-To-Conceive (TTC) Market

CDC PUBLIC HEALTH GRAND ROUNDS 2015, slide 36 titled “Impact of Lack of Insurance on Decision-Making”: Non-ART: $200 – $5,000 (and IVF: $10,000 – $15,000). Out-of-pocket costs can be substantial and impact patient decision-making and risk-taking – referring particularly to the IVF. (ART stands for Artificial Reproductive Technologies such as IVF, In Vitro Fertilization). We take $2,600 as the mean annual cost of TTC (Trying-To-Conceive, non-ART).

CDC Reproductive Health data last updated 2015: Number of US women ages 15-44 with impaired ability to get pregnant or carry a baby to term: 6.7 million or 10.9%. Number of US married women ages 15-44 who are infertile (unable to get pregnant after at least 12 consecutive months of unprotected sex): 1.5 million or 6.0%. The sum of the primary and secondary infertility sufferers in the U.S. is 8.2 million women. (Secondary infertility means that the mother has one child but cannot conceive for another.)

NIH Analysis of 277 Surveys 2012: Worldwide in 2010, 48.5 million couples were unable to have a child, of which 19.2 million couples were unable to have a first child (primary infertility), and 29.3 million couples were unable to have an additional child (secondary infertility, and the figure excludes China). Due to population growth, the number of couples suffering from infertility has increased since 1990, when 42.0 million couples were unable to have a child. Also, from WHO Evaluation Of Surveys 2004: More than 186 million ever-married women of reproductive age in developing countries were maintaining a “child wish”, translating into one in every four couples or 25%. We note this but opt for the NIH data, above.

Hence Our TTC Numerical Assumptions For the Minimum Value Scenario Are:

Number of US Fertility-Impaired Women Ages 15-44 is 8,200,000

US Serviceable Available Market $$ (at the TTC mean cost of $2,600 p.a.) is $21,320,000,000

US Serviceable Available Market $$ (at the TTC minimum cost of $200 p.a.) is $1,640,000,000

Worldwide Number of Women Who Are Unable to Have a Child is 48,500,000

Worldwide Total Available Market $$ is very large

E.g. if the estimate were based on the US non-ART cost average of $2,600 (see above), TAM is $126,100,000,000

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In closing, the reader is reminded that the above are the Assumptions for the bioZhena Minimum Value Scenario (Minimum Viable Product Scenario), which scenario represents the proverbial “low hanging fruit”. This is because our core product’s first application has FDA 510k clearance for aiding conception and for generating diagnostic menstrual profiles for physicians.

Our goal is to pursue the Full Value Scenario of the bioZhena Business Plan because of the potential of the bioZhena technology – summarized in the single slide here (the URL is:

https://biozhena.files.wordpress.com/2016/08/single-slide-biozhena-technology-potential-on-white-background1.pps ).

We aim to go well beyond personal reproductive management (which is, admittedly, where it all started, as evident from the whole bioZhena’s Weblog and our other web presence).

And for Investors – About PPM with business plan see https://biozhena.wordpress.com/and-for-investors-ppm/

And for more, you might check out  Home Page of bioZhena’s Weblog

bioZhena venture

bioZhena’s technology platform is bound to revolutionize women’s healthcare with diagnostic tools for women and their doctors & payers.

Empower women with clear menstrual cycle data vs. drugging healthy women & the iatrogenic consequences.

This is the first (sex-life management) application providing a superior (definitive) tool with which to tackle the ever-growing difficulty of getting pregnant when planned. And using the same tool for hormone-free, non-interventional, pregnancy avoidance. And, making available the 5th vital sign menstrual cycle profile signature to physicians when needed, for better diagnosis and management of health issues.

Also unprecedented and important for public health is our way of monitoring inconspicuously at the same self-check time the woman’s cervical health – at home. This will work in the background of the primary process, not bothering the user unless a tissue aberration is detected consistently several months in a row. This way of innocuous screening, and its affordability, should significantly improve on the Pap smear screening test.

Explore the few slides including the links in some of them: https://biozhena.files.wordpress.com/2017/03/new-mostly-narrated-slides-2017-03e2.pps

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But perhaps – especially if you are a male reader – you may feel that a daily (or almost daily) insertion for the quick self-check is too much to expect of a woman keen on knowing her daily fertility status plus the additional benefits of the routine?

Then our next generation telemetric cervical ring iteration of the same smart sensor is the answer for you. She and her doctor will have a choice.

See the image of a slide and click it to view the slide, grasp the significance:

https://biozhena.files.wordpress.com/2017/05/single-slide-friendly-tech-with-cervical-ring-ovulograph.pps

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But then my gynecology colleague would argue that the other major healthcare front is even more important. Namely, our way of providing to the women’s healthcare professionals access to the menstrual cycle vital sign longitudinal records, which Dr. Kim likened to the cardiologists’ ECG recordings – but with the important advantage of being affordably and routinely generated by patients at home (and saved in the sensor).

This other major front is providing to the healthcare system the means of obtaining a handle on the management of gynecologic and obstetric medical issues that require better diagnostic evidence for more effective and preventative therapies. In brief, we are answering the call and challenge to “Improve the methods and criteria to assess ovulatory dysfunction” (per R.S. Legro MD, 2013), and more.

Current modalities to diagnose preterm labor cannot detect the early biochemical changes of the cervix which result in dilation that leads to preterm births. Once the advanced signs of preterm labor are found, remedies to stop it are often futile and always costly for the healthcare system ($26B annually in USA alone), and frequently have adverse long-term consequences for the prematurely-born child and the family.

https://biozhena.files.wordpress.com/2014/11/impedence-beyond-cervical-length.pdf

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The bioZhena technology will alert the women-users and their healthcare providers on a timely basis to the onset of pregnancy-related conditions such as normal and preterm labor. And the immediate detection of pregnancy, whether intended or unintended, is automatic with the primary routine use of the home-use smart sensor. That is a notable advantage over the current home pregnancy tests!

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Summing up, read an overview Feasibility of the Planned Range of Ovulona™ Applications

https://biozhena.files.wordpress.com/2014/11/feasibility-of-the-planned-range-of-ovulona-applications1.pdf

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And here is now the financial pro forma aspect of bioZhena’s breakthrough non-interventional approach to women’s healthcare.

5-year pro forma assuming $6M funding (5-year Business Plan Summary Financial Projections)

Or, better,

10-year projections:

Minimum Viable Product Scenario (MVS) and Full Value Scenario (FVS)

For better legibility click https://biozhena.files.wordpress.com/2016/09/comparison-mvs-cf-fvs.pps

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From bioZhena’s pitch on EquityNet:

Women’s personal sex-life management tool for the Information Age.

Generating diagnostic vital-sign profiles for doctors and payers.

This first app of proprietary cervical sensor has FDA clearance.

Income from it will support further breakthrough applications.

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The gist of the bioZhena women’s healthcare breakthrough is this:

We monitor the brain – sex organs feedback loop.

Nobody else does.

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See the illustration below. Grasp the significance: The market offers you anything other than what’s needed, which is the monitoring of the feedback brain – ovary interactions.

“To mitigate the startup investment risk, the first app is an already FDA-cleared electronic fertility monitor for women at home…

Our electronic technology platform is bound to revolutionize women’s healthcare with diagnostic tools for women and their doctors & payers.

… will provide for non-interventional reproductive management, aiding conception and natural birth control without hormones, and automatically detecting pregnancy – planned or accidental. …

We will offer early detection of cervical cancer and other STDs as a built-in screen performed innocuously in the privacy of one’s home – automatically in the background of the primary monitoring…

Ovulona™ tracks the female reproductive cycle via the end-organ effect of the brain-ovary feedback loop on the uterine cervix. Numerous benefits ensue…”

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This is a screen shot of slide 4 from a 5-slide set https://lnkd.in/ed9yXUX

(slides take a few moments to open).

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Contra Nescience Contra Insouciance (SM 2015)

The Home Page of bioZhena’s Weblog offers further particulars (click the link, which translates as “Against Ignorance Against Indifference”)

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And yours truly bioZhena founder seeks a well-matched management partner of either gender.

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women’s health, reproductive management | Scoop.it

chagall_nativite_nesign.jpg

For a scoop of my 2015 blog posts on LinkedIn and a couple of other social media, click here: women’s health, reproductive management | Scoop.it.

If my Good Friday philippic denouncing the Pill and its consequences https://lnkd.in/bPZVWKV makes you wonder how all this could be possible, think of the history of the Pill development and use.

History: The Great Bluff That Led To A ‘Magical’ Pill And A Sexual Revolution http://www.npr.org/blogs/health/2014/10/07/354103536/the-great-bluff-that-lead-to-a-magical-pill-and-a-sexual-revolution.

Development & use: Why too many young and not so young ladies could NOT receive flowers on Mothers’ Day: Why so many trying-to-conceive, why so much infertility https://biozhena.wordpress.com/2012/05/14/why-too-many-young-and-not-so-young-ladies-could-not-receive-flowers-on-mothers-day-why-so-many-trying-to-conceive-why-so-much-infertility/

The short URL above, https://lnkd.in/bPZVWKV, stands for http://biozhena.tumblr.com/post/113125522418/recap-2-reason-why-a-non-hormonal-birth-control  Recap #2 reason why a non-hormonal birth control option is a good idea: It’s not all in the head – the bad effects of the Pill.

And the motto in my profile is Contra Nescience Contra Insouciance. It stands for Against Ignorance Against Indifference.

End of the year, and trying to get pregnant

Now, at the end of the year, …

“…Josef Lada did far more than illustrate the Hasek’s Good Soldier Svejk novel, and his idealized paintings of carol singers and family gatherings are, for many in this country, an enduring symbol of Czech Christmas.” http://www.radio.cz/en/section/curraffrs/josef-ladas-paintings-an-enduring-symbol-of-czech-christmas/pictures/obrazy/lada-josef/vanoce.jpg

…the stat counters monitoring the visits to the posts of bioZhena’s Weblog show something that I want to share with you. Namely: The most visited blog posts at this time of the year are those addressing the issues involved in trying to conceive (the flip side of natural birth control). Those blog articles exhibit distinctly higher viewing statistics than the stats of the posts on other topics of reproductive health – whereby some of those topics exhibit a different seasonality of increased interest.

If you wish to put this in context and review the situation out there, outside of bioZhena’s Weblog, read the attached paper Google evidence of increasing prevalence of subfertility.

A couple of examples of the bioZhena’s Weblog titles most visited at this time of the year:

The fallacy of ovulation calculators, calendars and circulating-hormone detectors = https://biozhena.wordpress.com/2012/02/13/the-fallacy-of-ovulation-calculators-calendars-and-circulating-hormone-detectors/ Don’t let them lead you by the nose with likely this and probable that! You need to know for sure.

Critique of birth control efficacies in NFP as published by Marquette University researchers = https://biozhena.wordpress.com/2010/03/23/critique-of-birth-control-efficacies-in-nfp-as-published-by-marquette-university-researchers/ Comments on a report of two studies http://www.usccb.org/prolife/issues/nfp/cmr_winter-spring09.pdf – they report on what we will call peri-ovulation methodologies.

Some women email me, while some “like” certain Ovulona pages or bioZhena’s Weblog posts.

Citing from one such email: “I am a 41 year old nulliparous woman in good health (with a few minor issues). I have been TTC for 1 year without success and came across Ovulona by accident during a Google search for how to optimise my fertility.”  TTC stands for Trying To Conceive, a standard acronym in the community of sub-fertility sufferers. Or even infertility sufferers – those who have not conceived while trying for longer than a year. (Re: Medical definitions of sub-fertility and infertility.) Nulliparous means no children, medical adjective for women having no previous births.

You know, my dear reader, that the optimal age for conception and motherhood is 20 to 24 years, after which fertility starts declining, and it drops a lot after 35 years of age. Should this be news to you, read The perils of IVF, of ARTs, of giving birth at old maternal age . “About epigenetic evidence that should make you think twice+ before you contemplate In Vitro Fertilization and think that having a baby can wait. The bottom line? Be a young mother!”

And from another reader’s email: “Please let me know if there is any way to buy an Ovulona or to use one for trial purposes.”

In response, I can only explain – apologetically, suppressing frustration – that we do not have any Ovulona units available because we have not yet manufactured the marketable product, due to lack of capital. Then, attempting a little more positive note, I remind the would-be Mums about what some experts call “focused intercourse” – that is focusing on trying to hit the fertile window. In the absence of the Ovulona, this must be done preferably with more than one of the several available methods (several, because they are unreliable, inaccurate – don’t rely on any one of them alone). And I urge you to also avoid stress…

Although the old imperfect methods (including instrumental monitoring of urine samples and/or of the BBT) give only inaccurate estimates, they should help to focus on the right time when the probability of conception exists. Outside of the fertile window you don’t have a chance to conceive.

Here is to illustrate two such imperfect methods in comparison with ours (where our Ovulona not only anticipates but also detects ovulation, which detection is all important): https://biozhena.wordpress.com/2007/12/16/cervix-uteri-and-seven-or-eight-related-things/marquette-comparison-with-lh-kit-and-peak-mucus-2/ .

In this record of a 42-years old woman, our device detected delayed ovulation on cycle day 17, while two other methods estimated ovulation from day 16 to day 18. This lack of precision and accuracy is not at all good for natural birth control and/or for trying to achieve fetal gender pre-selection (= trying to conceive specifically a boy or specifically a girl). But, with such inaccurate methods, which are available now before we bring the Ovulona into the market, you can see here that you might be fortunate and hit on at least a part of the fertile window. In this example (because of the ovulation delay), the LH-indicated days 16 and 17 were fertile days because the sperm are viable for about 3 days. Perhaps even day 18 may have been a fertile day, if the ovum (egg) lived long enough, and depending on when exactly on day 17 the detected ovulation occurred (morning or evening?). Such uncertainties will be removed by properly designed experiments with the properly designed Ovulona.

This record from a comparative study shows how the old ovulation prediction methods are unreliable, because the two used here predicted ovulation for 3 different days – but the record may also serve to illustrate for you that (and how) you may be lucky and hit at least one of the fertile days. Here, in this record, ovulation was detected – not merely anticipated – by the Ovulona prototype. It was detected on the day of the second urinary LH indication, which is here one day before the esoteric Peak mucus of NFP aficionados; they did not use the BBT in this study. None of the old techniques detects ovulation: they predict it or, in the case of the BBT, indicate that ovulation has occurred.

There are only 3 days in each menstrual cycle during which pregnancy can occur, and it will if you are fortunate. The 3 fertile days are the day of ovulation plus the two days immediately before ovulation.

I’ll now write a long sentence full of the word “trying”, with several connotations. Repeat after me (and grasp what follows): Trying to determine the 3 days of the fertile window without the Ovulona is pretty much impossible, but trying for it – or at least some of it – is better than trying completely in the dark.

That’s because the 3-day fertile window varies, it does not stay put on certain days of the menstrual cycle from one cycle to the next. Check out this earlier bioZhena post for evidence that this is so. See evidence generated by other experts years or rather decades ago – when they hoped that microcomputer-assisted basal body temperature [BBT] monitoring would solve the problem.

From a graph such as the one above, it is evident that to determine the fertile days before ovulation is more difficult than estimating the last fertile day, which is the day of ovulation. This difficulty is a well recognized fact, and it’s not a matter of whether ovulation is or is not delayed by stress of one kind or another. The stress-caused delay (or even complete suppression) of ovulation is one of the things that complicate management of reproductive life.

Now for the encouragement: Maybe, the idea of not being completely at the mercy of chance when trying to conceive a baby, might even help you to be less stressed out about it at a time when celebrating the end of the year (and looking back and looking forward – along with all that Christmas rush) leads to an increased level of stress anyway.

Josef Lada’s idyllic take on Christmas activities in the countryside and in the city, that is to say, in Czechoslovak towns of his day. There, a fish meal on Christmas Eve was and still is one of the traditions, although the country is now two (and good friends). The fishy thing was apparently based on the belief that fish scales symbolize the prospect of money next year to the eater. Maybe some of us should not have turned our nose up about this fish thing… Then the capital for the Ovulona might not have been so slow coming! Mea culpa, mea maxima culpa!

Perhaps the focus idea may help you not to be stressed out about the thing which is supposed to be pleasurable and not a chore. Suppose that between now and some time in January/February (in the course of the long winter evenings, “za dlouhych zimnich veceru”) you’ll get your focusing organized. You surely will get over the holidays, too… Then, with a bit of happiness, relaxation and luck, come next October you will have the kind of happiness you wish for! And you’ll thus contribute to the birth/delivery statistics for October…

Josef Lada’s calendar illustration for October (c. 1940s)

In this picture, Josef Lada illustrated, long time ago, the characteristics of the month of October. Among them is the rut of the elk, which had given the month its name in the artist’s language. Way back, in those days – the pre-contraceptive Pill days, years and centuries – the difficulty to become pregnant was not a widespread phenomenon, and Mums were  younger than many are nowadays.

The evolution of subfertility and infertility (as a big-time societal phenomenon) in the U.S. is summarized based on data from http://www.infoplease.com/ipa/A0005074.html#ixzz2GBMSkUKy  [Information Please® Database, © 2007 Pearson Education, Inc.] in the next post.

What is the mechanism of stress and how does it affect reproduction. An update. And: Be a young mother!

Ovulona™-related published scientific findings by others about disruption of fertility, about PCOS or Poly Cystic Ovarian Syndrome, how stress suppresses ovulation, about the hypothalamic amenorrhea of stress and postpartum blues/depression, about a CRH placental clock which determines the length of gestation and the timing of parturition and delivery, and the role of CRH in premature labor. How old age affects folliculogenesis as a stressor. Even how acute stress may induce ovulation in women.

This is an update in May 2012 on scientific literature reviewed in biozhena.wordpress.com/2007/12/27/   For an easier read (as opposed to the excerpts from scientific papers) you may want to go to Stress and Your Fertility at http://natural-fertility-info.com/stress-and-your-fertility.html but Hethir’s article does not refer to the Ovulona™. It simply tells you that stress has a negative effect on your chances of getting pregnant.

Unlike in the 2007 blog post, in the present update I share the complete abstracts of publications (way further down), pointing out in the abstracts certain details by bold font highlighting. On occasion I also point out in bold italics after the given abstract how the paper relates to the bioZhena project and the Ovulona™ personal monitor.

But first, I offer summary comments on the relationship of given papers to the bioZhena project, along with some details excerpted from the abstracts. Search result item numbers are indicated – so you can correlate my summary with the full abstracts and references shown below (after the Alfons Mucha picture).

In March 2018 I am adding here for reference the links to the page on the Ovulona (as updated in 2017)

https://biozhena.wordpress.com/2007/12/11/the-ovulona/

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For the latest bioZhena Weblog post (as of June 2019) on Stress And Fertility, Fertile Window, Ovulation, go to  https://biozhena.wordpress.com/stress-and-fertility-fertile-window-ovulation/

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Now to the subject of the present post, the review of Ovulona™-related scientific findings published by others, which suggest possible women’s healthcare applications of the technology:

Item 16:

This paper is suggestive of the prospective diagnostically beneficial use of the Ovulona™ in the management of PCOS [Poly Cystic Ovarian Syndrome], expected to be possible due to PCOS-caused alteration of the cyclic profile (detected via the exocervix, as the cervix monitors the integrated effects of all the hormones).

… effect is mediated by the hypothalamus, as evidenced by similar LH release in response to exogenous GnRH. This may represent the physiological condition that underlies ovarian follicular cysts.

Item 22.-related:

By emphasizing the critical timing of stress, this paper points by implication at the importance of routine Ovulona monitoring of Folliculogenesis In Vivo™, particularly  for assisting women who have difficulty to conceive but also for those practicing natural birth control. In either case, detecting any delay of ovulation is crucial.

The effects of stress on reproduction depend on the critical timing of stress, the genetic predisposition to stress, and the type of stress. The effect of stress on reproduction is also influenced by the duration of the responses induced by various stressors. Prolonged or chronic stress usually results in inhibition of reproduction, while the effects of transient or acute stress in certain cases is stimulatory…

Item 43:

This paper is related to our finding of delayed ovulation in some of the experimental subjects of two pilot studies of Ovulona™ prototypes – an important and unique feature of the Ovulona monitor, considering our way of life, full as it is of stress and not only stress of the psychological kind.

… findings support the hypothesis that stress-like increments in plasma cortisol [= increasing amounts of cortisol in blood] interfere with the follicular phase by suppressing the development of high frequency LH pulses, which compromises timely expression of the preovulatory estradiol rise and LH and FSH surges.

Item 67:

Again, the listed paper is related to the PCOS problem, as is the next publication.

A follicle becomes cystic when it fails to ovulate and persists on the ovary. Secretion of GnRH/LH from the hypothalamus-pituitary is aberrant, which is attributed to insensitivity of the hypothalamus-pituitary to the positive feedback effect of oestrogens. Altered metabolite and hormone concentrations may influence follicle growth and cyst development.

You will see below, in the full abstracts of the papers, that the reported experiments could not be performed with human subjects, and the last two abstracts selected from the veterinary literature search state the following.

Item 101:

Imposition of an experimental stressor suppresses GnRH/LH pulse frequency and amplitude. It is not yet clear whether delays in the surge are caused by interruption of the oestradiol signal-reading phase, the signal transmission phase or GnRH surge release. [Note: oestradiol is British spelling of estradiol, the most predominant form of estrogen.]

Item 102:

Glucocorticoids are vital to many aspects of normal brain development, but fetal exposure to superabundant glucocorticoids can result in life-long effects on neuroendocrine function. … Precise levels of glucocorticoids are required for proper gonadal function; where the balance is disrupted, so is fertility.

What follows now is an analogous summary of the subsequent search on human (as opposed to animal) female fertility and stress.

Reviewing the few full abstracts with references, below, is highly recommended.

Item 3:

… These effects are responsible for the “hypothalamic” amenorrhea of stress, which is observed in anxiety and depression, malnutrition, eating disorders and chronic excessive exercise, and the hypogonadism of the Cushing syndrome. … Reproductive corticotropin-releasing hormone is regulating [those] reproductive functions [that have] an inflammatory component, such as ovulation, luteolysis, decidualization, implantation, and early maternal tolerance. … Postpartum, this hypercortisolism is followed by a transient adrenal suppression, which may explain the blues/depression and increased autoimmune phenomena observed during this period.

Item 3.-related:

Acute stress may induce ovulation in women. … acute-stress-induced release of LH is found under relatively high plasma levels of estradiol. … Women may be induced to ovulate at any point of the menstrual cycle or even during periods of amenorrhea associated with pregnancy and lactation if exposed to an appropriate acute stressor under a right estradiol environment.

Item related to the above:

The stress system has suppressive effects on female and male reproductive function. Corticotrophin-releasing hormone (CRH), the principal regulator of stress, has been identified in the female and male reproductive system. … It has been suggested that there is a “CRH placental clock” which determines the length of gestation and the timing of parturition and delivery. … animal studies to elucidate the role of CRH in… premature labor.

Two literature search results – whereby I consider old age to be a stressor – are noted (with only certain excerpts from the abstracts) at the end of the post, consistent with the previously proposed motto: Be a young mother!

Hints for why – WHY TO BE A YOUNG MOTHER (besides coping more easily with other stressors) – cited from said two papers:

#1. Impaired folliculogenesis and ovulation in older reproductive-age women.

#2. Women in their 20s and 30s should be counselled about the age-related risk of infertility when other reproductive health issues, such as sexual health or contraception, are addressed as part of their primary well-woman care. Reproductive-age women should be aware that natural fertility and assisted reproductive technology success (except with egg donation) is significantly lower for women in their late 30s and 40s. Women should be informed that the risk of spontaneous pregnancy loss and chromosomal abnormalities increases with age. END OF QUOTE.

Alfons Mucha – Maude Adams as Joan of Arc, 1909
http://en.wikipedia.org/wiki/File:Mucha-Maud_Adams_as_Joan_of_Arc-1909.jpg

Literature search was initially performed as Related Articles for http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=Link&LinkName=pubmed_pubmed&from_uid=10844239  = What is stress, and how does it affect reproduction?

Dobson H, Smith RF. Anim Reprod Sci. 2000 Jul 2;60-61:743-52. Review.

PMID: 10844239 [PubMed – indexed for MEDLINE] Related citations

Selecting articles more recent than 2000 (search result numbers indicated). Most of these articles – in the initial search – are reports about animal models. (The reported work is obviously also for the benefit of agribusiness – for its reproduction-dependent profitability.)

16.

An alteration in the hypothalamic action of estradiol due to lack of progesterone exposure can cause follicular cysts in cattle.

PMID: 12021048 [PubMed – indexed for MEDLINE]

Free Article

Related citations

Biol Reprod. 2002 Jun;66(6):1689-95.

An alteration in the hypothalamic action of estradiol due to lack of progesterone exposure can cause follicular cysts in cattle.

Gümen A, Wiltbank MC.

Department of Dairy Science, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.

Abstract

Many mammals, including cattle, can develop ovarian follicular cysts, but the physiological mechanisms leading to this condition remain undefined. We hypothesized that follicular cysts can develop because estradiol will induce a GnRH/LH surge on one occasion but progesterone exposure is required before another GnRH/LH surge can be induced by estradiol. In experiment 1, 14 cows were synchronized with an intravaginal progesterone insert (IPI) for 7 days, and prostaglandin F(2alpha) was given on the day of IPI removal. Estradiol benzoate (EB; 5 mg i.m.) was given 3 days before IPI removal to induce atresia of follicles. Cows were given a second EB treatment 1 day after IPI removal to induce a GnRH/LH surge in the absence of an ovulatory follicle. All cows had an LH surge following the second EB treatment, and 10 of 14 cows developed a large-follicle anovulatory condition (LFAC) that resembled follicular cysts. These LFAC cows were given a third EB treatment 15 days later, and none of the cows had an LH surge or ovulation. Cows were then either not treated (control, n = 5) or treated for 7 days with an IPI (n = 5) starting 7 days after the third EB injection. Cows were treated for a fourth time with 5 mg of EB 12 h after IPI removal. All IPI-treated, but no control, cows had an LH surge and ovulated in response to the estradiol challenge. In experiment 2, cows were induced to LFAC as in experiment 1 and were then randomly assigned to one of four treatments 1) IPI + EB, 2) IPI + GnRH (100 microg), 3) control + EB, and 4) control + GnRH. Control and IPI-treated cows had a similar LH surge and ovulation when treated with GnRH. In contrast, only IPI-treated cows had an LH surge following EB treatment. Thus, an initial GnRH/LH surge can be induced with high estradiol, but estradiol induction of a subsequent GnRH/LH surge requires exposure to progesterone. This effect is mediated by the hypothalamus, as evidenced by similar LH release in response to exogenous GnRH. This may represent the physiological condition that underlies ovarian follicular cysts.

This paper is suggestive of the prospective diagnostically beneficial use of the Ovulona™ in the management of PCOS [Poly Cystic Ovarian Syndrome] due to PCOS-caused distortion of the cyclic profile.

Sue Coe – Feed Lot, 1991, stone lithograph
http://www.graphicwitness.org/coe/feedlot.jpg

22.-related (found as a related article of a related article)

Acta Vet Scand. 2008 Dec 10;50:48.

Stress and its influence on reproduction in pigs: a review.

Einarsson S, Brandt Y, Lundeheim N, Madej A.

PMID: 19077201 [PubMed – indexed for MEDLINE]

Free PMC Article

Division of Reproduction, Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Box 7054, SE-75007 Uppsala, Sweden. stig.einarsson@kv.slu.se

Abstract

The manifestations of stress, defined as a biological response to an event that the individual perceives as a threat to its homeostasis, are commonly linked to enhanced activity of the hypothalamo-pituitary-adrenal (HPA) axis and the activation of the sympathetic adreno-medullary (SA) system. Activation of the HPA system results in the secretion of peptides from the hypothalamus, principally corticotropin releasing hormone (CRH), which stimulates the release of adrenocorticotropic hormone (ACTH) and beta-endorphin. ACTH induces the secretion of corticosteroids from the adrenal cortex, which can be seen in pigs exposed to acute physical and/or psychological stressors. The present paper is a review of studies on the influence of stressors on reproduction in pigs. The effects of stress on reproduction depend on the critical timing of stress, the genetic predisposition to stress, and the type of stress. The effect of stress on reproduction is also influenced by the duration of the responses induced by various stressors. Prolonged or chronic stress usually results in inhibition of reproduction, while the effects of transient or acute stress in certain cases is stimulatory (e.g. anoestrus), but in most cases is of impairment for reproduction. Most sensitive of the reproductive process are ovulation, expression of sexual behaviour and implantation of the embryo, since they are directly controlled by the neuroendocrine system.

This paper suggests the importance of routine monitoring of Folliculogenesis In Vivo™ for assisting women who have difficulty to conceive.

43.

Endocrine basis for disruptive effects of cortisol on preovulatory events.

PMID: 15625239 [PubMed – indexed for MEDLINE]

Free Article

Related citations

Endocrinology. 2005 Apr;146(4):2107-15. Epub 2004 Dec 29.

Endocrine basis for disruptive effects of cortisol on preovulatory events.

Breen KM, Billings HJ, Wagenmaker ER, Wessinger EW, Karsch FJ.

Reproductive Sciences Program, University of Michigan, 300 North Ingalls Building, Room 1101 SW, Ann Arbor, Michigan 48109-0404, USA. breenk@umich.edu

Abstract

Stress activates the hypothalamo-pituitary-adrenal axis leading to enhanced glucocorticoid secretion and concurrently inhibits gonadotropin secretion and disrupts ovarian cyclicity. Here we tested the hypothesis that stress-like concentrations of cortisol interfere with follicular phase endocrine events of the ewe by suppressing pulsatile LH secretion, which is essential for subsequent steps in the preovulatory sequence. Cortisol was infused during the early to midfollicular phase, elevating plasma cortisol concentrations to one third, one half, or the maximal value induced by isolation, a commonly used model of psychosocial stress. All cortisol treatments compromised at least some aspect of reproductive hormone secretion in follicular phase ewes. First, cortisol significantly suppressed LH pulse frequency by as much as 35%, thus attenuating the high frequency LH pulses typical of the preovulatory period. Second, cortisol interfered with timely generation of the follicular phase estradiol rise, either preventing it or delaying the estradiol peak by as much as 20 h. Third, cortisol delayed or blocked the preovulatory LH and FSH surges. Collectively, our findings support the hypothesis that stress-like increments in plasma cortisol interfere with the follicular phase by suppressing the development of high frequency LH pulses, which compromises timely expression of the preovulatory estradiol rise and LH and FSH surges. Moreover, the suppression of LH pulse frequency provides indirect evidence that cortisol acts centrally to suppress pulsatile GnRH secretion in follicular-phase ewes.

This paper is related to our finding of delayed ovulation in some of the experimental subjects of two pilot studies of Ovulona™ prototypes.

67.

Aetiology and pathogenesis of cystic ovarian follicles in dairy cattle: a review.

Vanholder T, Opsomer G, de Kruif A.

Reprod Nutr Dev. 2006 Mar-Apr;46(2):105-19. Epub 2006 Apr 6. Review.

PMID: 16597418 [PubMed – indexed for MEDLINE]

Free Article

Related citations

Reprod Nutr Dev. 2006 Mar-Apr;46(2):105-19. Epub 2006 Apr 6.

Aetiology and pathogenesis of cystic ovarian follicles in dairy cattle: a review.

Vanholder T, Opsomer G, de Kruif A.

Department of Reproduction, Obstetrics and Herd Health, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium.

Abstract

Cystic ovarian follicles (COF) are an important ovarian dysfunction and a major cause of reproductive failure in dairy cattle. Due to the complexity of the disorder and the heterogeneity of the clinical signs, a clear definition is lacking. A follicle becomes cystic when it fails to ovulate and persists on the ovary. Despite an abundance of literature on the subject, the exact pathogenesis of COF is unclear. It is generally accepted that disruption of the hypothalamo-pituitary-gonadal axis, by endogenous and/or exogenous factors, causes cyst formation. Secretion of GnRH/LH from the hypothalamus-pituitary is aberrant, which is attributed to insensitivity of the hypothalamus-pituitary to the positive feedback effect of oestrogens. In addition, several factors can influence GnRH/LH release at the hypothalamo-pituitary level. At the ovarian level, cellular and molecular changes in the growing follicle may contribute to anovulation and cyst formation, but studying follicular changes prior to cyst formation remains extremely difficult. Differences in receptor expression between COF and dominant follicles may be an indication of the pathways involved in cyst formation. The genotypic and phenotypic link of COF with milk yield may be attributed to negative energy balance and the associated metabolic and hormonal adaptations. Altered metabolite and hormone concentrations may influence follicle growth and cyst development, both at the level of the hypothalamus-pituitary and the ovarian level.

Again, the paper is related to the PCOS problem, as is the next publication.

67.-related (found as a related article)

Formation of follicular cysts in cattle and therapeutic effects of controlled internal drug release. [J Reprod Dev. 2006]

J Reprod Dev. 2006 Feb;52(1):1-11.

Formation of follicular cysts in cattle and therapeutic effects of controlled internal drug release.

Todoroki J, Kaneko H.

Kimotsuki Livestock Hygiene Service Center, Kanoya, Kagoshima, Japan.

Abstract

Follicular cysts in cattle result from excessive growth of the dominant follicle without ovulation and still constitute a major reproductive disorder in this species. One key hormonal characteristic of cows with follicular cysts is the lack of an LH surge, although they have increased plasma estradiol concentrations. Another is a relatively high level of pulsatile secretion of LH that promotes continued growth of the dominant follicle. These LH characteristics seem to result from a functional abnormality in the feedback regulation of LH secretion by estradiol. Treatment with controlled internal drug release devices that increase circulating progesterone levels is effective in resolving follicular cystic conditions by 1) lowering pulsatile LH secretion and 2) restoring the ability of the hypothalamo-pituitary axis to generate an LH surge in response to an increase in circulating estradiol.

PMID: 16538030 [PubMed – indexed for MEDLINE]

Free full text

101.

Effects of stress on reproduction in ewes.

Dobson H, Fergani C, Routly JE, Smith RF.

Anim Reprod Sci. 2012 Feb;130(3-4):135-40. Epub 2012 Jan 26.

PMID: 22325927 [PubMed – in process]

Related citations

Anim Reprod Sci. 2012 Feb;130(3-4):135-40. Epub 2012 Jan 26.

Effects of stress on reproduction in ewes.

Dobson H, Fergani C, Routly JE, Smith RF.

School of Veterinary Science, University of Liverpool, Leahurst Campus, Neston, Wirral, United Kingdom. hdobson@liv.ac.uk

Abstract

Stressors, such as poor body condition, adverse temperatures or even common management procedures (e.g., transport or shearing) suppress normal oestrus behaviour and reduce ewe fertility. All these events are co-ordinated by endocrine interactions, which are disrupted in stressful situations. This disruption is usually temporary in adult ewes, so that, when prevailing conditions improve, normal fertility would resume. Imposition of an experimental stressor (shearing, transport, isolation from other sheep, injection of endotoxin or insulin or cortisol infusion) suppresses GnRH/LH pulse frequency and amplitude. Part of the cause is at the pituitary, but effects on GnRH/LH pulse frequency and the GnRH/LH surge are mediated via the hypothalamus. It is not yet clear whether delays in the surge are caused by interruption of the oestradiol signal-reading phase, the signal transmission phase or GnRH surge release. Stressors also delay the onset of behaviour, sometimes distancing this from the onset of the pre-ovulatory LH surge. This could have deleterious consequences for fertility.

CAPT. AJIT VADAKAYIL’s two images of stressed out women
Via Google search on “stressed woman in modern art painting”
These two images are from Ship Captain Ajit Vadakayil
http://ajitvadakayil.blogspot.com/2011/02/modern-abstract-art-and-picasso-capt.html
Original sources:
Weeping Woman by Pablo Picasso (1937)
http://www.inminds.com/weeping-woman-picasso-1937.html
and
untitled file saved as AASHIK+1+001.jpg
http://4.bp.blogspot.com/-NijqSqXo2Tw/TVkVQkpCmII/AAAAAAAADcU/rzleByUNJfg/s1600/AASHIK+1+001.jpg

102.

Glucocorticoids, stress, and fertility.

Whirledge S, Cidlowski JA.

Minerva Endocrinol. 2010 Jun;35(2):109-25. Review.

PMID: 20595939 [PubMed – indexed for MEDLINE]

Related citations

Minerva Endocrinol. 2010 Jun;35(2):109-25.

Glucocorticoids, stress, and fertility.

Whirledge S, Cidlowski JA.

Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health/DHHS, Research Triangle Park, Durham, NC 27709, USA.

Abstract

Modifications of the hypothalamo-pituitary-adrenal axis and associated changes in circulating levels of glucocorticoids form a key component of the response of an organism to stressful challenges. Increased levels of glucocorticoids promote gluconeogenesis, mobilization of amino acids, and stimulation of fat breakdown to maintain circulating levels of glucose necessary to mount a stress response. In addition to profound changes in the physiology and function of multiple tissues, stress and elevated glucocorticoids can also inhibit reproduction, a logical effect for the survival of self. Precise levels of glucocorticoids are required for proper gonadal function; where the balance is disrupted, so is fertility. Glucocorticoids affect gonadal function at multiple levels in hypothalamo-pituitary-gonadal axis: 1) the hypothalamus (to decrease the synthesis and release of gonadotropin-releasing hormone [GnRH]); 2) the pituitary gland (to inhibit the synthesis and release of luteinizing hormone [LH] and follicle stimulating hormone [FSH]); 3) the testis/ovary (to modulate steroidogenesis and/or gametogenesis directly). Furthermore, maternal exposure to prenatal stress or exogenous glucocorticoids can lead to permanent modification of hypothalamo-pituitary-adrenal function and stress-related behaviors in offspring. Glucocorticoids are vital to many aspects of normal brain development, but fetal exposure to superabundant glucocorticoids can result in life-long effects on neuroendocrine function. This review focuses on the molecular mechanisms believed to mediate glucocorticoid inhibition of reproductive functions and the anatomical sites at which these effects take place.

At this point, let’s change the search tactics, by looking at Related Citations for this last one, which is clearly about human (as opposed to animal) female fertility and stress: http://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&DbFrom=pubmed&Cmd=Link&LinkName=pubmed_pubmed&IdsFromResult=20595939

3.

Stress and the female reproductive system.

Kalantaridou SN, Makrigiannakis A, Zoumakis E, Chrousos GP.

J Reprod Immunol. 2004 Jun;62(1-2):61-8. Review.

PMID: 15288182 [PubMed – indexed for MEDLINE]

Related citations

J Reprod Immunol. 2004 Jun;62(1-2):61-8.

Stress and the female reproductive system.

Kalantaridou SN, Makrigiannakis A, Zoumakis E, Chrousos GP.

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Ioannina, School of Medicine, Panepistimiou Avenue, 45500 Ioannina, Greece.

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis, when activated by stress, exerts an inhibitory effect on the female reproductive system. Corticotropin-releasing hormone (CRH) inhibits hypothalamic gonadotropin-releasing hormone (GnRH) secretion, and glucocorticoids inhibit pituitary luteinizing hormone and ovarian estrogen and progesterone secretion. These effects are responsible for the “hypothalamic” amenorrhea of stress, which is observed in anxiety and depression, malnutrition, eating disorders and chronic excessive exercise, and the hypogonadism of the Cushing syndrome. In addition, corticotropin-releasing hormone and its receptors have been identified in most female reproductive tissues, including the ovary, uterus, and placenta. Furthermore, corticotropin-releasing hormone is secreted in peripheral inflammatory sites where it exerts inflammatory actions. Reproductive corticotropin-releasing hormone is regulating [those] reproductive functions [that have] an inflammatory component, such as ovulation, luteolysis, decidualization, implantation, and early maternal tolerance. Placental CRH participates in the physiology of pregnancy and the onset of labor. Circulating placental CRH is responsible for the physiologic hypercortisolism of the latter half of pregnancy. Postpartum, this hypercortisolism is followed by a transient adrenal suppression, which may explain the blues/depression and increased autoimmune phenomena observed during this period.

Georg Scholz – Nightly Noise, 1919
http://tigtail.org/TIG/M_View/TVM/B/European/b.%20between%20wars/German-Austrian/expressionism-2-1.html

3.-related (found as Cited by 7 PubMed Central articles)

Reprod Biol Endocrinol. 2010 May 26;8:53.

Acute stress may induce ovulation in women.

Tarín JJ, Hamatani T, Cano A.

Department of Functional Biology and Physical Anthropology, Faculty of Biological Sciences, University of Valencia, Burjassot, Valencia 46100, Spain. tarinjj@uv.es

Abstract

BACKGROUND:

This study aims to gather information either supporting or rejecting the hypothesis that acute stress may induce ovulation in women. The formulation of this hypothesis is based on 2 facts: 1) estrogen-primed postmenopausal or ovariectomized women display an adrenal-progesterone-induced ovulatory-like luteinizing hormone (LH) surge in response to exogenous adrenocorticotropic hormone (ACTH) administration; and 2) women display multiple follicular waves during an interovulatory interval, and likely during pregnancy and lactation. Thus, acute stress may induce ovulation in women displaying appropriate serum levels of estradiol and one or more follicles large enough to respond to a non-midcycle LH surge.

METHODS:

A literature search using the PubMed database was performed to identify articles up to January 2010 focusing mainly on women as well as on rats and rhesus monkeys as animal models of interaction between the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes.

RESULTS:

Whereas the HPA axis exhibits positive responses in practically all phases of the ovarian cycle, acute-stress-induced release of LH is found under relatively high plasma levels of estradiol. However, there are studies suggesting that several types of acute stress may exert different effects on pituitary LH release and the steroid environment may modulate in a different way (inhibiting or stimulating) the pattern of response of the HPG axis elicited by acute stressors.

CONCLUSION:

Women may be induced to ovulate at any point of the menstrual cycle or even during periods of amenorrhea associated with pregnancy and lactation if exposed to an appropriate acute stressor under a right estradiol environment.

PMID: 20504303 [PubMed – indexed for MEDLINE]

PMCID: PMC2890612

Free PMC Article

Max Beckmann, The rape of Europa, ca. 1933
http://www.online-literature.com/forums/showthread.php?p=1050088

The above-related (found via their Ann N Y Acad Sci. 2006 Dec;1092:310-8 abstract titled “Reproductive” corticotropin-releasing hormone).

J Reprod Immunol. 2010 May;85(1):33-9.

Corticotropin-releasing hormone, stress and human reproduction: an update.

Kalantaridou SN, Zoumakis E, Makrigiannakis A, Lavasidis LG, Vrekoussis T, Chrousos GP.

Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Ioannina Medical School, Ioannina, Greece. Sophia_Kalantaridou@hotmail.com

Abstract

The stress system has suppressive effects on female and male reproductive function. Corticotrophin-releasing hormone (CRH), the principal regulator of stress, has been identified in the female and male reproductive system. Reproductive CRH participates in various reproductive functions that have an inflammatory component, where it serves as an autocrine and paracrine modulator. These include ovarian and endometrial CRH, which may participate in the regulation of steroidogenesis and the inflammatory processes of the ovary (ovulation and luteolysis) and the endometrium (decidualization and blastocyst implantation) and placental CRH, which is secreted mostly during the latter half of pregnancy and is responsible for the onset of labor. It has been suggested that there is a “CRH placental clock” which determines the length of gestation and the timing of parturition and delivery. The potential use of CRH-antagonists is presently under intense investigation. CRH-R1 antagonists have been used in animal studies to elucidate the role of CRH in blastocyst implantation and invasion, early fetal immunotolerance and premature labor. The present review article focuses on the potential roles of CRH on the physiology and pathophysiology of reproduction and highlights its participation in crucial steps of pregnancy, such as implantation, fetal immune tolerance, parturition and fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis.

Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

PMID: 20412987 [PubMed – indexed for MEDLINE]

NOTA BENE or NOTE WELL: Chancy search result #1 (in our book, old age is a stressor):

J Clin Endocrinol Metab. 2003 Nov;88(11):5502-9.

Impaired folliculogenesis and ovulation in older reproductive aged women.

Santoro N et al.

… to test the hypothesis that older reproductive age [ORA >or= 45 yr old] women ovulate at a smaller follicle diameter and are more likely to produce multiple follicles during their menstrual cycle compared with mid-reproductive age [MRA 22-34 yr old] women. … ORA women were twice as likely to have multiple follicles as younger women. … grossly abnormal hormonal patterns were observed in some of the ORA women’s cycles. Other cycles demonstrated a failure of folliculogenesis. ORA women ovulated at a smaller mean follicle diameter … than younger women.

NOTA BENE or NOTE WELL: Chancy search result #2 (old age being a stressor):

J Obstet Gynaecol Can. 2011 Nov;33(11):1165-75.

Advanced reproductive age and fertility.

Reproductive Endocrinology and Infertility Committee; Family Physicians Advisory Committee; Maternal-Fetal Medicine Committee; Executive and Council of the Society of Obstetricians, Liu K, Case A.

Recommendations (excerpted from Abstract):

1. Women in their 20s and 30s should be counselled about the age-related risk of infertility when other reproductive health issues, such as sexual health or contraception, are addressed as part of their primary well-woman care. Reproductive-age women should be aware that natural fertility and assisted reproductive technology success (except with egg donation) is significantly lower for women in their late 30s and 40s.

2. Because of the decline in fertility and the increased time to conception that occurs after the age of 35, women > 35 years of age should be referred for infertility work-up after 6 months of trying to conceive.

…

5. Pregnancy rates for controlled ovarian hyperstimulation are low for women > 40 years of age.

6. The only effective treatment for ovarian aging is oocyte donation. A woman with decreased ovarian reserve should be offered oocyte donation as an option, as pregnancy rates associated with this treatment are significantly higher than those associated with controlled ovarian hyperstimulation or in vitro fertilization with a woman’s own eggs.

7. Women should be informed that the risk of spontaneous pregnancy loss and chromosomal abnormalities increases with age. Women should be counselled about and offered appropriate prenatal screening once pregnancy is established.

8. Pre-conception counselling regarding the risks of pregnancy with advanced maternal age, promotion of optimal health and weight, and screening for concurrent medical conditions such as hypertension and diabetes should be considered for women > age 40.

9. Advanced paternal age appears to be associated with an increased risk of spontaneous abortion and increased frequency of some autosomal dominant conditions, autism spectrum disorders, and schizophrenia. Men > age 40 and their partners should be counselled about these potential risks when they are seeking pregnancy, although the risks remain small.

Durer’s Wife Agnes by Albrecht Durer, about 1494
http://www.albrecht-durer.org/Durer%27s-Wife-Agnes.html

Although this literature search update is not necessarily complete, the blog post has grown long enough, so we better stop here. Enough food for thought for now… Don’t let all this stress you out! Just keep in mind: Be a young mother!

Oh, and do tell Uncle Rockefeller that Auntie Katharine (McCormick) made a little Big Mistake when she put her bets on chemistry and Cousin Margaret’s “magic pill”.

Why too many young and not so young ladies could NOT receive flowers on Mothers’ Day: Why so many trying-to-conceive, why so much infertility

Say thank you to the social and medical advances of the twentieth century – primarily those of chemical birth control, the Pill.

Yes, chalk it to the great advancements! Sarcasm aside, indisputable developments in society and in medicine have resulted in the present state of affairs.

Incidentally, “Mothers’ Day (with the plural) is how it was spelled in the U.S. congressional resolution first recognizing it, 9 May 1908”. That was before all this started, before Margaret Sanger wrote “What Every Girl Should Know”, before she started a radical feminist monthly “The Woman Rebel”, and released 100,000 copies of “Family Limitation”. It was before “her confrontational style attracted even greater publicity for herself and the cause of birth control.”

Margaret Sanger
http://www.nyu.edu/projects/sanger/secure/aboutms/index.html
She wanted to liberate women.

Some years later, in the late 1920s – early 1930s, the Japanese Dr. Kyusaku Ogino (Professor at Niigata, Japan) and Dr. Hermann Knaus in Austria (University Women’s Clinic in Graz, Austria) independently discovered that women can conceive only during a brief period “in the middle of the menstrual cycle” [The Eugenics Review: Volume 28, 1936]. But – while this was the fundamental discovery of the menstrual cycle – pretty much right away there was the similarly fundamental criticism that “the so-called safe period of Knaus and Ogino offers very small protection indeed”.

That was because, for reproductive management, “the theories of Knaus and Ogino have not yet been proved sufficiently reliable for us to recommend the so-called safe period as a method of contraception…” although, “if the theory is correct, there will be more likelihood of impregnation at this time.”

Ngram 11 showing the number of English-language books with the phrase Knaus and Ogino between the years 1900 and 2008 (the latest year of available data; at smoothing 3 )
http://books.google.com/ngrams/graph?content=Knaus+and+Ogino&year_start=1900&year_end=2008&corpus=0&smoothing=3
The second, higher, peak is indicative of the relationship between the practical failure of Ogino and Knaus and the inception of the oral contraceptive pill, which provided the answer to the failure.              (For the record, the following 2008 books give good reviews of the Ogino-Knaus story in the history of reproductive management: http://books.google.com/books?id=sqwMrennRsQC&pg=PA205&dq=%22Knaus+and+Ogino%22&hl=en&sa=X&ei=39uzT5uYKeWq2QXGmrDpCA&ved=0CEgQ6AEwAg#v=onepage&q=%22Knaus%20and%20Ogino%22&f=false     AND     http://books.google.com/books?id=RmpMZ7K2L3YC&pg=PA142&dq=%22Knaus+and+Ogino%22&hl=en&sa=X&ei=JsiyT6zXCKbM2AXf3-DpCA&ved=0CEIQ6AEwAQ#v=onepage&q=%22Knaus%20and%20Ogino%22&f=false   —    found via   https://www.google.com/search?q=%22Knaus%20and%20Ogino%22&tbs=bks:1,cdr:1,cd_min:1997,cd_max:2008&lr=lang_en)

Then again, “there is a good deal of evidence to prove the existence of these fertile and sterile periods”, and an author in 1945 “gives his opinion that the period during which the mammalian egg is susceptible to fertilization may be measured”.

It was eventually – only in recent years – recognized that the extent of the fertile period should be only 3 days, and that the basic practical problem was the variability of the menstrual cycle, essentially of the follicular (“proliferative”) phase, the one before ovulation.

However, at the time we were not around with the Ovulona™ to measure the fertile period, and Mrs. Sanger’s zeal took her in the direction of a “magic pill”. In view of the failure of the first effort at natural approach to reproductive management, the so-called rhythm method, her direction is not too surprising because it was the time of great pharmaceutical advances. The chemists had the bandwagon of steroid chemistry to ride and Dr. Gregory Pincus had pioneered in vitro fertilization in the rabbit, for which he was not admired but more or less ostracized.

“In 1953, Margaret Sanger and Katharine McCormick (a heir to major millions of dollars) confronted Pincus with the idea of creating an oral contraceptive”, and the rest is history – of the Pill. History of the oral contraceptive pill and the ensuing sexual revolution. Do check out under P (Pill, the) in the Alphabet of bioZhena, and don’t miss also under M the article about “Mysterious conceptions (OR THE NONEXISTENCE THEREOF)”.

And then – now – there are the consequences of the Pill, one of which translates as the absence of the mother status in the lives of many women desiring motherhood. Those who are unsuccessfully trying to conceive, and so the bouquets of Mothers’ Day are only for their Moms.

Look how there was no infertility and no IVF before contraception. See the blue curve of infertility in the bottom graph, and the green curve of IVF in the top graph of books plotted against the years of the 20th century. See how they go up only years after the rise of contraception (bottom) and after birth control and family planning (top).

Ngrams 12 and 3 together showing the number of English-language books with the phrases birth control, family planning and IVF (Ngram 12, top) and contraception and infertility (Ngram 3, bottom)
between the years 1900 and 2008 (the latest year of available data; at smoothing 3 )
Ngram 3 data from http://books.google.com/ngrams/graph?content=birth+control&year_start=1900&year_end=2008&corpus=0&smoothing=3 , and Ngram 12 data (note: twice as high amplitude, top graph) from http://books.google.com/ngrams/graph?content=birth+control%2Cfamily+planning%2CIVF&year_start=1900&year_end=2008&corpus=0&smoothing=3

I have discussed the consequences of the steroid chemical contraception technology in several posts in this bioZhena’s Weblog. The consequences are numerous because of the far-reaching significance of tinkering with reproductive physiology – consequences for women’s health, and for public health.

Far-reaching consequences because the naturally occurring and functioning hormones, which the contraceptives tinker with, are essential for the functioning of the female organism, for the well-being of every woman.

Check out the Table of Contents = links to bioZhena posts. See, for example:

About atrophy, reproductive aging, and how it’s really not nice to fool Mother Nature – or with (For people outside of NFP [Natural Family Planning] because NFP people know this already)

The perils of IVF, of ARTs, of giving birth at old maternal age. (About epigenetic evidence that should make you think twice+ before you contemplate In Vitro Fertilization and think that having a baby can wait. The bottom line? Be a young mother!)

Difficult to conceive – Google evidence that pregnancy complications and trying-to-conceive concerns shot up after the Pill launch in 1960s (Regardless of what contraceptive proponents tell you)

Along the way to the unfortunate consequences of the anti-ovulation, anti-conception Pill and its modifications (modified methods of delivery of the chemicals into the female organism) there has been the effort to replace the calendar or rhythm method with different means of prediction of the ovulation day. I am referring to Natural Family Planning (NFP) and/or to the somewhat more recently labeled Fertility Awareness Based Methods (FABMs), one of which is the Fertility Awareness Method (FAM) itself. Fertility awareness – as opposed to the calendar – is key.

Some proponents will include NFP within FABMs and, of course, define NFP as requiring sexual abstinence during the fertile phase (aka fertile window) of the menstrual cycle; as opposed to FAM, which is defined as the use of a barrier method of contraception (such as a condom) during the fertile phase (fertile window).

Either way, the extent of the fertile window has always been THE major issue or rather the issue has always been the need for accurate and reliable determination of the fertile days. Only our Ovulona can determine the mere 3 fertile days due to the lifetimes of the sperm and of the ovum, egg. No other technique can.

Natural Family Planning or more broadly the FABMs cannot win if they continue to rely on what I have called (politely) the peri-ovulation methods of guesstimating the fertile window.

Whether used to assist conception or to avoid it, ovulation calculators, calendars and circulating hormone detectors will not do.

Scientific Fertility Assessment™ based on Follliculogenesis In Vivo™ is the only way to stop the unhealthy chemicalization of reproductive health management.

Gil Bruvel, Relative Time (1993)
http://www.liveinternet.ru/tags/surrealism/page7.html
An interesting title. Each woman has her own biological clock, which responds to her circumstances in every individual menstrual cycle. That is why there is no such thing as cycle regularity (despite the long-held simplistic belief to the contrary).
In 1970, Dr. Hugh J. Davies of Johns Hopkins University told the US Senate in the Nelson Hearings about the contraceptive Pill: “Never before in history have so many people taken such powerful medication with so little information as to its actual and potential risks. …With the introduction of such active ingredients, we are actually setting up a massive endocrinological experiment with millions of healthy women.”

Natural family planning was a significant refinement of the fundamental discovery of Ogino and Knaus, developed as an alternative to the artificial chemical contraception. For decades the NFP proponents, along with OBGYNs and birth control advocates, erred on the (off-putting) long side of guesstimating the fertile window from various signs of the approach of ovulation.

Before it was officially – and incorrectly – decided in 1995 that there were 6 fertile days (all before and including the ovulation day), the period of abstinence required by NFP was advocated as at least 10 or 13 days long. A bit too much, to say the least – and, naturally, without monitoring the variable pre-ovulation phase to quantitatively anticipate ovulation, the failure rate was too high for birth control.

Logically, the same goes for “the other side of the coin”, for conception and pregnancy achievement. Again, please see certain other posts in this blog for more – you’ll recognize the pertinent articles in the table of contents.

One example of such a post is “Major studies decades ago revealed variability of menstrual cycles” (But people are still naïve about the basic cause of the difficulty to achieve pregnancy).

The NFP and FABM approaches to birth control have managed to avoid being nicknamed “the Vatican roulette” – unlike the rhythm/calendar method of Ogino and Knaus, the pioneers of the fertile and sterile periods who discovered the menstrual cycle.

However, without our Ovulona™ the NFP and other fertility awareness methods are not reliable and, despite the NFP popularity in numerous countries, they are not any more suitable for birth avoidance than “the Vatican roulette”. Without the definitive determination of the fertile days, they are not approved for avoiding conception, and tend to be utilized for aiding conception.

That’s because, in the proceptive use (promoting conception), the methods’ lack of reliability only translates into an extended time of trying to conceive rather than into an unwanted pregnancy. Only!

Fertility awareness tends to be utilized for aiding conception by “focused intercourse” because of the high prevalence of the difficulty to conceive. And the “focus” is about all that those methods do, which helps – even if at least half is misfocused, if you take my meaning, if you see what I mean. The probability of conception increases with focus on the fertile window of opportunity. That’s fundamental, too.

People have a hard time accepting that getting pregnant is not as easy as expected, when they finally decide to want a baby – usually way too late, and after her use of the Pill. The drug makes healthy young women in their best years to postpone family- baby-making, it damages their cervical S-crypts thus causing difficulty to conceive and, by encouraging promiscuous sex life, it has caused an enormous increase in the prevalence of sexually transmitted diseases that also lead to infertility. Not just a double whammy, a triple whammy on womankind.  Sad, sad, sad.

The underlying principle of the predicament of unfulfilled yearning for a baby is highlighted in the second half of the caption accompanying the Toyen painting just below – an image of futile waiting. (Highlight extracted as the briefest of summaries from https://biozhena.wordpress.com/2010/05/25/difficult-conception-tied-to-pregnancy-complications-addressed/.)

 

Toyen, Spící (1937)
http://kultura.idnes.cz/podivejte-se-jak-vypada-marne-cekani-od-toyen-ktere-se-drazi-za-20-milionu-1ak-/vytvarneum.aspx?c=A090312_102133_vytvarneum_jaz
The painting’s title means Sleeping. The title of the referenced source, a media article, says : Look what futile waiting by Toyen looks like…
See Description of the image file for more about Toyen: https://biozhena.wordpress.com/2012/05/14/why-too-many-young-and-not-so-young-ladies-could-not-receive-flowers-on-mothers-day-why-so-many-trying-to-conceive-why-so-much-infertility/toyen-spici-1937/
It is not likely that Toyen would have had this in mind, but I present her art to highlight the predicament of unfulfilled yearning for a baby.
To highlight this:The chances of becoming pregnant are critically dependent on whether the insemination (natural or artificial) occurs at the right time, within the fertile window. This is because the probability of pregnancy is a combination of four individual probabilities:    1. Probability of being in good health,    2. of successful insemination,    3. of not miscarrying the conceptus (early embryo), and    4. the probability of correct timing of the baby-making intercourse. For example, a 60% success rate of correct timing brings the overall probability of pregnancy down to a mere 36%, and this goes down to a mere 30% if correct timing probability is only 50%, in healthy fertile couples – assuming the probability #3 (not miscarrying the conceptus) at an optimistic 75%. Even if the probability of determining the insemination time correctly were 90%, the resulting probability of successful pregnancy from any one particular insemination event would be only 55%. Get this! Only 55% under perfect ideal conditions, which include a young healthy unstressed woman.

Advanced age of the would-be Mum works against her on account of the Mother Nature’s Probabilistic Rules and Regulations of Baby-Making: Good health and successful insemination probabilities are degraded whereupon the strict Natural Eugenicist [i.e. Mother Nature] suppresses the conceptus.

So that, most often, the hCG pregnancy marker does not even have a chance to be detected – after the nerve-wracking 2-week wait – by the not-so-young Mum-candidate’s HPT [Home Pregnancy Test].

Needless to say that, all the more the not-so-young motherhood aspirant needs to enhance the fourth element of the equation, the probability of correct timing of the hoping-for-baby sexual intercourse.

And all this because the young lady used the Pill during the years best suited for baby-making, and as a consequence she is not-so-young any more. It’s not nice to fool Mother Nature! Or with…

Therefore, I conclude this blog post by disputing the positive and admiring message in the concluding paragraph in the above-cited article “The Birth of The Pill”. They write: “Margaret Sanger dreamt of the idea of a birth control pill since she was a young woman. If she wasn’t confined to the boundaries of her time, she and McCormick could’ve researched and funded The Pill without the help of any male doctors or scientists. Unfortunately, the society that they lived in would not allow them to do so; they did go as far as they could. Many of their achievements go unnoticed, but both women were really the leading forces behind the development of The Pill.” QUOTE UNQUOTE.

Yes, indeed, Margaret Sanger and Katharine McCormick were the leading forces in the inception of chemical contraception. Driven by a social, political agenda (with “can do” in lieu of the needed biomedical insight), they imposed on women, and hence on humankind, a simple-minded solution “as simple as taking an aspirin”. But, then… the consequences … among them an enormous increase in the incidence of sexually transmitted infections, contributing to the epidemic of infertility.

And that’s only for openers, as the saying goes. Referring to https://biozhena.wordpress.com/2012/04/18/the-perils-of-ivf-of-arts-of-giving-birth-at-old-age-part-2/: Detrimental effects on the offspring and – via epigenetics – on the health of future generations. Iatrogenic medicine kicking Hippocrates where it hurts the most. Also, therefore, quite the opposite effects with respect to the eugenic vision of Mrs. Sanger. Ironic, isn’t it.

The perils of IVF, of ARTs, of giving birth at old age – part 2

Tidbits from a debate at LinkedIn group The Life Science Executive Exchange, about DANGERS OF IN VITRO FERTILIZATION. Since many of you will not be members of said group, I make bits from the discussion available in this way, for the interested reader. And I offer Google Ngram evidence for why I was justified to exclaim, “Damn the bloody Pill”.

Politely put as: Perish the Pill! The drug (aka Oral Contraceptive Pill, OCP, and its various modifications) created the problem that too many solve with IVF and other ARTs (= In Vitro Fertilization and other Artificial Reproductive Technologies). People debate hotly burdening future generations with debt – but we don’t seem to care about burdening them with health consequences of the daft but so prevalent postponement of motherhood until it’s too late.

In January 2017 it is appropriate to add one other angle to the concern about as yet unproven but possible consequences of artificial reproduction. When “sperm are injected directly into an unfertilized egg, [the ART procedures] are bypassing nature’s way of eliminating defective sperm…” Dr. Gagneux told the American Association for the Advancement of Science in Washington. “The concern is that by by-passing female choice (or filter) at the level of sperm selection, we might produce embryos that contain risk factors that we would otherwise not have.”

Thus reported in popular media (http://www.independent.co.uk/news/science/ivf-use-could-be-storing-up-health-problems-biologist-warns-a6875876.html?platform=hootsuite), while in one of their scientific publications Eillen Tecle and Pascal Gagneux write in specialist language about “female choice, whereby females actively select more advantageous sperm… based on the glycocalyx variability as a metric of sperm quality… Evidence exists for selective processes by cervical mucus…  retention of sperm with compromised chromatin in the cervical mucus… remains to be formally investigated” (http://onlinelibrary.wiley.com/doi/10.1002/mrd.22500/full).

And now back to the LinkedIn debate about the epigenetic concern regarding IVF and other ARTs.

Vanya Loroch:

“…our behavior impacts directly the health of our descendants. Not much to do with Darwin, by the way (for those who do not know what epigenetics is all about). …

The issues we face today in our world are often so complex that lay people CANNOT blindly trust experts (IVF protocols or FUKUSHIMA are two very different examples… but maybe not that different, come to think about it). If we want a better world for our children, it may be absolutely essential to build a trans-disciplinary knowledge and society where lay people are educated ENOUGH to throw the right questions at the experts and make informed decisions together.

Agnes Boulloche – L’Education

WE NEED REAL UNIVERSAL LIFE SCIENCE EDUCATION FOR ALL (what 99% of the people are getting is a sad joke). If we fail to achieve this, utter irrationality (e.g. the GMO debate in Europe) or worse (unnecessary suffering) are bound to happen, again and again.”

Patrick Courtney:

“Why is the GMO debate in Europe utter irrationality?”

Vanya Loroch:

“…I have a very short answer. When European citizens are asked whether a tomato contains DNA, the majority (65%, I believe) answer NO – ref. below. These frightening numbers are going down but very slowly… If the GMO debate is a citizen debate, as IT SHOULD BE, 65% of the citizens cannot be rational about it because they lack even the most basic understanding of the workings of a living cell. …”

References:
1. Eurobarometer survey. See for example: http://genome.wellcome.ac.uk/doc_WTD021020.html
2. A wealth deferred: the politics and science of Golden Rice. Erin Baggott . Harvard International Review/Fall, 2006

Paul Stinson:

“What rubbish. Are you telling me that Swiss scientists in 2011 studying IVF results (from what years?) are being taken seriously? I am familiar with a couple that had IVF treatment in Johannesburg in 1991 and their twin sons are today Varsity Squash team members in an Ivy League school. Vascular dysfunction? I doubt it.”

Vanya Loroch:

“If it is rubbish, it is peer-reviewed rubbish and it took several years to peer-review it.

And the outcome is that the publisher (Circulation, Journal of the American Heart Association – Impact factor almost as good as the impact of Science[top US journal]) took the study and the results seriously enough to publish it. 65 healthy kids born thanks to IVF + lab model on mice all show the same issues: epigenetic alterations + abnormal vascular structure and function, similar to what some type I diabetics have (or worse). Maybe rubbish to you, but data are always data. By the way, vascular dysfunction doesn’t mean one can’t excel in sports. It’s a risk factor, not a disease!

If interested, read the paper or at least the abstract, eg. Conclusions: Healthy children conceived by ART display generalized vascular dysfunction. This problem does not appear to be related to parental factors, but to the ART procedure itself. http://circ.ahajournals.org/content/early/2012/03/13/CIRCULATIONAHA.111.071183.abstract?goback=.gde_72923_member_103918763

And remember that hydrogenated fats were promoted by the medical experts in the seventies and eighties as a healthy alternative to animal fats. To err is human….”

[My added comment: The royal physicians of the British King George V recommended cigarette smoking as a healthy and useful activity – in second decade of 1900s. How many decades before the change of heart?]

Romer A. Gonzalez-Villalobos:

“I personally think that it is too early to jump into any conclusions. Science is self correcting; let’s wait and see if other studies support these findings.”

Vanya Loroch:

“I agree that we certainly don’t have the full picture, but the mouse IVF model the team developed replicates faithfully the epidemiological findings in the children.

The vascular damage in IVF can be fully prevented by including melatonin during the in vitro step.

This vascular damage is passed on to F1 mice. The methylation of promoter regions in key genes needed for vasculogenesis and arteriogenesis was shown to be altered, and butyrate fed to the IVF mice prevented the transmission of the dysfunctional artery phenotype to the offspring.

Agnes Boulloche – Dessins

In other words, very different experimental techniques to characterize the phenomenon all say the same thing: epigenetic alterations at the time when gametes/early embryo are suspended in synthetic media, in vitro.

Science is self-correcting, but that is not necessarily true for human health. For me (and I have no potential conflict of interest with anyone or anything), the results of the human and mouse studies are more than enough to declare an immediate moratorium on IVF and ICSI until this issue of epigenetic alterations is solved. Of course this is unlikely to happen. I only hope that the health of all the IVF kids will not be adversely affected by what has been seen.”

My comment: He has an omission in the above statement in that the concern – about the epigenetic consequences for health of subsequent generations of the offspring – is not expressed. It’s not merely or even mainly about the IVF kids. Do see the BBC movie to grasp this – referenced in part 1: The Ghost in your Genes (at http://www.youtube.com/watch?v=toRIkRa1fYU ). 5 video clips of some 9 minutes or so each. The epigenetic consequences last for generations.

Meanwhile, here is evidence for how it all came about, why the problem arose in the first place. Before the introduction of the contraceptive Pill, IVF did not exist. Are you familiar with the word iatrogenic?

Ngram 9: in vitro fertilization, IVF, the Pill, OCP
http://books.google.com/ngrams/graph?content=in+vitro+fertilization%2CIVF%2Cthe+Pill%2C+OCP&year_start=1960&year_end=2008&corpus=0&smoothing=5
When you enter phrases into the Google Books Ngram Viewer, it displays a graph showing how may times those phrases have occurred in a corpus of books (here English-language books) over the selected years (here 1960 to 2008). The N numbers (or the number of phrase occurrences relative to all books) for the four topics are on the same scale indicated on the vertical axis. The graph shows that the number of books about the Pill (green) goes up after the Pill launch in the early 1960s and, after leveling off in late 1970s, it starts declining. Meanwhile, the number of books on OCP (Oral Contraceptive Pill, yellow curve) grows as the OCP term becomes more and more used in medico-scientific literature, leveling off in the 1990s and then declining (similar to the green curve of the Pill). The number of books on IVF (red) has grown well above the book numbers on the other terms or phrases, including “in vitro fertilization” (blue), which was understandably at first somewhat more frequent than “IVF” but from early 1980s “IVF” has been the preferred term and thus the number of books about IVF by far exceeds those on the other three terms/topics.
Whether ”IVF” or “in vitro fertilization”, it is clear from this Ngram that books on the subject did not exist before chemical contraception was introduced in the 1960s.
This is possibly seen more easily below in Ngram 10, which only shows the data for books on IVF (blue) and for books about the Pill (red), same as in Ngram 9. Books about the Pill appear and grow in numbers in the 1960s while IVF books only appear and their volume grows fast some 10 years later. Another decade later, the IVF book numbers far exceed those about the Pill. Also significantly, the IVF book volume does not exhibit a declining trend.

Ngram 10: IVF and the Pill

The Pill was never a good medication, if only because pregnancy is not a disease. It’s always been a drug of convenience, and we don’t even have to go into the eugenic intentions of Mrs. Sanger, without whom her “magic pill” of a drug would not have come about. A drug of convenience is akin to recreational drugs.

Instead of messing with women’s reproductive biochemistry and physiology, healthcare and public health should have focused, and should focus now, on behavioral reproductive management. (As in: You want to feel good? Go for a run, raise your endorphins and burn some calories – but don’t do drugs. Same difference with the Pill. Don’t bust up your cervical physiology with the Pill, making for your infertility. You won’t need to worry about Clomid, IVF etc. if you watch your age, too.) But now back to the discussion of Dangers of In Vitro Fertilization.

Heber Hammon:

“This was a very interesting and sobering article. I have been surprised at the reaction of the medical profession regarding it. I think the epigenetic system needs to be studied closely. I suspect the recent autism epidemic is caused to a high degree by malfunction of the epigenetic processes. We have learned that nutrition plays an important role. I follow IVF from the perspective of animal science. I have not seen any health issues resulting from embryo transplanting either from embryo flushing or implanting after IVF. The discussion here is informative on many levels.”

Mike Kelly:

“As a follower of IVF science for many years I do not understand how you can make a statement that melatonin will alleviate the symptoms discovered. I sense some lack of scientific verity.”

Vanya Loroch:

“Mike, this is not a “statement”, it is an experimental finding made by the team in their mouse IVF model. They were the first ones to be surprised.

The finding is the following: the inclusion of melatonin in the culture media (the in vitro step) normalized DNA methylation of the embryos; it prevented in particular the dysmethylation of the promoters of genes needed for arteriogenesis, and it also prevented mesenteric endothelial dysfunction and arterial hypertension.

This finding is in mouse IVF so far. Extrapolating to humans is the usual issue.

Melatonin *is known* to play an (important?) role in regulation of ovarian function, it plays a favorable role in oocyte maturation and it improves fertilization rates. This is well documented. A Pubmed search (“melatonin in vitro fertilization”) or even Google will point you to the relevant literature.

My comment for you here:

For confirmation see search http://isearch.avg.com/search?cid={6AE0129D-5975-485B-BB40-4646A7CCE716}&mid=a0d3a7b6b0f32c95be0fb17758cc560e-b42e229379060869383d6811e0f2b34960104ea5&ds=AVG&lang=us&v=10.2.0.3&pr=fr&d=2012-02-14%2019:21:29&sap=dsp&q=melatonin+in+vitro+fertilization

Citing from the first search result (J Pineal Res. 2000 Jan;28(1):48-51): Melatonin increased the fertilization rate significantly… Furthermore, a significant increase in the rate of embryos reaching the four-cell stage, the eight-cell stage, and blastulation, was observed. [Quantitative data are omitted by me here.]

From a related citation (Endocr Res. 2010 Jan;35(1):17-23): Melatonin is capable of improving the developmental capacity of ovine, porcine and bovine embryos in vitro. … The in vitro development of mouse two-cell embryos significantly benefited from treatment with melatonin in a concentration-dependent manner…

Derek Donohue:

”Plenty of facts and data exist to support this finding.

I’d encourage everyone to look at this from a standpoint of a discipline with a longer history and larger dataset – horse breeding. Fact is people pay far more to breed a champion racehorse than they do to breed a human. Yet this high dollar industry, far pre-dating the human fertility industry, is fraught with failure and error. Only a handful of legacy champions have ever been bred in countless attempts.

Furthermore, issues surrounding sperm and egg viability have yet to be overcome by even the most modern science.

Emotions and energy in the chaos aesthetic by Viktor Sheleg
http://www.sheleg-gallery.com/sheleg2/index1.htm
or http://ego-alterego.com/wp-content/uploads/2011/07/40881_111467795583097_100001596316201_102626_6451116_n.jpg

We are only now coming to full understanding of the scope of genomic function occurring within sperm, including their genetic expression to environmental stressors. The experts in that field agree this is likely at the root of historically disappointing fertilization rates from frozen equine sperm. But we’ve only just begun to even look at it. [Interjecting my comment: With our technology, they could avoid semen freezing and bring the stallion to the mare at the right time in her estrous cycle, even trying for the desired fetal sex.]

With this in mind, I am fully open to believing that we don’t have the full understanding of the entire topic of human fertility that we like to believe we do.

Which of you can tell me how frozen human sperm samples are thawed? In the equine world it is dunked in a 50C water bath for up to 5 minutes. This, despite the fact that millions of years of evolution have put the testes outside of the body because even temps of 37C are stressful to sperm. This common mammalian attribute has remained constant ahead of many other evolutionary changes in countless species. Yet, despite this glaring evidence, this egregiously unscientific practice is the widely accepted standard in a discipline with a six figure buy in.

Can any of you really vouch for the quality of donated human sperm when half million dollar equine sperm is handled so haphazardly? Does anyone really claim to already know that donor sperm is not similarly genetically compromised by environmental stressors even when we are just now realizing that the possibility exists? Resting in self assurance of that which is known, while ignoring all that is not known, that is not the way to advance scientific understanding.

We’ve barely just started looking at the genetic impacts of IVF practices inside of eggs and sperm despite long understanding that we are asking them to function the same under totally foreign conditions.

Keep in mind, the question is not can you put an egg and sperm together in a dish and get a viable offspring. The question is can you produce the same quality offspring at the same rate as the real thing. To be convinced that we can, when we’ve only begun exploring the most fundamental factors, that is not a rational or fact based position. Especially when we cannot even follow nature’s multimillion year example of how to handle sperm.

I’m willing to accept these results, encourage further study, and endeavor to understand the how and why in the interest of improving outcomes. END QUOTE

MARINA RICHTEROVÁ – Golgota, Hommage a P. Bruegel, 1998 and The Juliet, 2000
From http://www.gallery.cz/gallery/en/Vystava/1999_01/Ramec_V.html

This concludes the selection from the referenced LinkedIn discussion at The Life Science Executive Exchange, titled DANGERS OF IN VITRO FERTILIZATION.

I close with the words with which I opened part 1 of this topic about epigenetic evidence that should make you think twice before you contemplate In Vitro Fertilization and mainly before you think that having a baby can wait. The bottom line? Be a young mother!

The perils of IVF, of ARTs, of giving birth at old maternal age

About epigenetic evidence that should make you think twice+ before you contemplate In Vitro Fertilization and think that having a baby can wait. The bottom line? Be a young mother!

I lighten up this very serious topic by announcing that an unusually early hummingbird scout has arrived here in the Front Range of northern Colorado Rocky Mountains yesterday morning! And the tiny hummie is here today, too! In fact, two of them, the green-back variety!

But on Friday, it was a sad coincidence when, after I “shared” on Facebook the picture of a certain baby in need of a heart transplant, later in the day I happened on a related news. And I tweeted the allowed 140 characters thus: #Infertile #TryingToConceive Warning & clear explanation http://to.ly/cTP3 #IVF protocols seriously flawed – induce epigenetic damage.     

Sarah Christie, Facebook – Share this! If she gets 1,000 shares she gets her heart transplant for free.
http://www.facebook.com/photo.php?fbid=388139167870098&set=a.318579008159448.96351.100000220538357&type=1&ref=nf

In the above-linked summary of a Swiss study about children born by Artificial Reproductive Technology [ART] procedures, “ART children were found to have … a significantly higher risk of cardiovascular disease at a young age.”

Note: “Vascular dysfunction is related to ART per se rather than to parent-related factors. Oxidative stress may represent an underlying mechanism”. Cited from: “Systemic Vascular Dysfunction in Children Conceived by Assisted Reproductive Technologies” http://spo.escardio.org/eslides/view.aspx?eevtid=33&id=976 by Rimoldi SF, Sartori C, demarche SF, Stuber T, Garcin S, Duplain H, Germond M, Scherrer U, Allemann Y.

See also: “Systemic and Pulmonary Vascular Dysfunction in Children Conceived by Assisted Reproductive Technologies”, Circulation 2012; CIRCULATIONAHA.111.071183 published online before print March 20 2012 by Urs Scherrer et al. – http://circ.ahajournals.org/content/early/2012/03/13/CIRCULATIONAHA.111.071183.abstract : “…children conceived by ART display generalized vascular dysfunction. This problem does not appear to be related to parental factors, but to the ART procedure itself.”

This Circulation 2012 online article also summarizes the background, as follows: “Assisted reproductive technology (ART) involves the manipulation of early embryos at a time when they may be particularly vulnerable to external disturbances. Environmental influences during the embryonic and fetal development influence the individual’s susceptibility to cardiovascular disease raising concerns regarding the potential consequences of ART on the long-term health of the offspring.”

And it is apparently even worse.

According to a position statement by European Society for Human Reproduction and Embryology (ESHRE), http://www.eshre.eu/binarydata.aspx?type=doc&sessionId=2zn3zp4523tjjg45tnjhaev1/Birth_defects_position_papers.pdf QUOTE:

“Children from couples who get pregnant after assisted reproduction techniques (ART), like IVF/ICSI, have a 40-50% increased risk for a birth defect.

A similar increased risk has been reported for subfertile couples who get pregnant spontaneously after a prolonged time period. This increased risk seems thus mainly be due to parental characteristics from the infertility status and not to the treatment given. A recent case-control study from USA has confirmed these findings.” END QUOTE.

Vanya Loroch, PhD is the author of the summary referenced in the tweet above, in the opening sentence about epigenetic damage due to IVF. Readers will benefit from watching his last listed reference, The Ghost in your Genes (at http://www.youtube.com/watch?v=toRIkRa1fYU ).  As Dr. Loroch writes, it is a fascinating BBC show on the topic of human epigenetics. I would say, the movie should be a mandatory infotainment (viewing) material for all teenagers and young adults.

Vanya also provides a micro-primer on epigenetic alterations, which I recommend. It is at the mentioned http://www.loroch.ch/blog/public/danger-ivf-summary-findings (= the above-cited tweet’s short URL: http://to.ly/cTP3 ).

Intuition – Gil Bruvel
http://www.liveinternet.ru/tags/surrealism/page7.html

As one of the scientists there contemplates, in the last part of the film, this new epigenetic insight will make you think about being a guardian of your genome – for the sake of the future offspring of your offspring, not just for your own health’s sake. The environmental impact on the health of future generations (yes, in plural) is demonstrated there in a clear way, with very little scientific jargon and much BBC quality.

Incidentally, how the in vitro in IVF causes the epigenetic switch (damage) is shown there, too. Highly recommended. They don’t even mention uniparental disomy (UPD) as I do, below! After you’ve watched the movie, you’ll put it in context, for sure. Especially you, the female “uniparent”!

I’ve written previously about delayed parenting or, rather, mothering: Every year past the optimal fertile age of early twenties is making things harder – on would be Mom, on Baby, on healthcare system, on humankind. Consequences of conception difficulties should not be taken lightly (ref.: https://biozhena.wordpress.com/2010/05/25/difficult-conception-tied-to-pregnancy-complications-addressed/ ). “High-risk pregnancies are more likely in women who have difficulty getting pregnant, with or without help from hi-tech fertility treatments.” That’s citing a specialist medical authority.

In my Facebook Note, titled “Bestia triumphans II and the International Women’s Day. A heresy?”, I put it rather mildly:

Ironically, the consequences of the sexual revolution [i.e., the introduction of the Pill in the 1960s] can only lead to the deterioration of the health of the human lot. The offspring of all those older mothers (and fathers) can hardly be expected to carry an improving human gene pool.

Jiří Anderle / Jiri Anderle
Bestia triumphans II
lept, měkký kryt / etching, vernis mou
1984, opus 271, 65 x 95,5 cm
34.000,- Kč / CZK
http://www.galerieart.cz/prodej_anderle_2.htm
For the “triumphant beast” and Giordano Bruno’s story see http://twitpic.com/8r5lyi or click for the image Description

One of the references behind this statement is: Am J Med Genet. 2000 Dec 18; 95(5):454-60, “The contribution of uniparental disomy to congenital development defects in children born to mothers at advanced childbearing age”: This study confirms the hypothesis that uniparental disomy is a not negligible cause of congenital developmental anomalies in children of older mothers. QUOTE UNQUOTE.

Brief clarifications:

Uniparental disomy (UPD) occurs when a newborn receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent (http://en.wikipedia.org/wiki/Uniparental_disomy ).

Maternal Age: Women are born with all the eggs they will ever have. Therefore, when a woman is 30 years old, so are her eggs. … Errors can crop up in the eggs’ genetic material as they [the eggs, ova] age over time. Therefore, older women are more at risk of giving birth to babies with chromosome abnormalities than younger women. Since men produce new sperm throughout their life, paternal age does not increase the risk of chromosome abnormalities (http://www.genome.gov/11508982 ).

Jiří Anderle
Láska za lásku / Love for Love
lept, pastel / etching, pastel, 1996
opus 535, 13 x 17 cm 7.400,- Kč / CZK
http://www.galerieart.cz/anderle_vystava_2011- 1990-1999.htm

Heresy or not, I exclaim in the vernacular used during my early adult years in Britain: Damn the bloody Pill!

And, from my even younger years in the “Old Country”, I recall the sadly funny outcry, Lide jsou blbe!, which translates – albeit without rhyming – as: People are imbecile! (daft, idiotic, …). These days, I would not use such language, of course. Not even to those whose job it is to look after healthcare.

The reasons for why I swear at the Pill and other Endocrine Disruptive Chemicals have been discussed previously in this bioZhena’s Weblog. See, for example, Difficult to conceive – Google evidence that pregnancy complications and trying-to-conceive concerns shot up after the Pill launch in 1960s (Regardless of what contraceptive proponents tell you) . You need the gist of the bad Pill effect, here and now? This is the bottom line: “After 3 and up to 15 months of contraceptive pill use, there is a greater loss of the S crypt cells than can be replaced. … S crypts are very sensitive to normal and cyclical stimulation by natural estrogens, and the Pill causes atrophy of these crypts. Fertility is impaired…” and people wait with having kids until it’s too late.

While the Pill- and other drug-making and the various artificial reproductive technologies are a big business (much like war-making), I continue to try and clarify that natural reproductive women’s health management is a must. Gentlemen, we do have the technology for that. Ladies, quite a few of them, already know. Or at least a few of them do – globally. Look at the Blog Stats and the Flag Counter, on the right margin (of home page or of about page).

Smoking affects the menstrual cyclic profile as captured by the Ovulona™, monitoring might help with smoking-cessation

80 percent of the 201,773 women who die prematurely from tobacco-related illnesses each year began smoking while they were adolescents. Evidence shows that those young people, who begin to use tobacco, do not understand the nature of the addiction. They believe they will be able to avoid the harmful consequences of tobacco use. They don’t know that “some researchers feel nicotine is as addictive as heroin. In fact, nicotine has actions similar to heroin and cocaine, and the chemical affects the same area of the brain.”

As someone has written, when most girls begin smoking, they are usually caught up in the immediate experience of what appears to be a “cool”, “adult”, or even “glamorous” behavior. They are naive about the powerful addictive nature of nicotine, which, for some adolescents, takes hold after only a few cigarettes.  Among those who had tried to quit smoking, 82 percent were unable to do so.

Alfons Mucha – Job, 1896      Previously shown in https://biozhena.wordpress.com/2010/05/25/difficult-conception-tied-to-pregnancy-complications-addressed/

The tobacco industry spends vast sums of money on persuading people to take up or continue smoking. In its own words, the industry is “a monster which has to be fed”. The industry sees women as a territory to be conquered, and a large portion of the total marketing expenditure is aimed in their direction.

Women appear to be more susceptible to the addictive properties of nicotine and have a slower metabolic clearance of nicotine from their bodies than do men. Women also appear to be more susceptible to the effects of tobacco carcinogens than men, including higher rates of lung cancer.

Girls and women are significantly more likely than boys and men to feel dependent on cigarettes, and more likely to report being unable to cut down on smoking. While various smoking-cessation treatments and strategies appear to work similarly for both sexes, women may face different stressors and barriers to quitting smoking, such as greater likelihood of depression, weight control concerns, and child-care and family issues.

It is estimated that about 30% of deaths from cervical cancer are caused by smoking. Smoking and taking the Pill in combination can increase the risk of heart disease by up to ten times.

Jiří Anderle, Láska za lásku / Love for Love lept, pastel / etching, pastel, 1996, opus 535, 13 x 17 cm 7.400,- Kč / CZK

Smoking is damaging to women’s reproductive health. It is associated with infertility, complications during pregnancy, and an earlier onset of menopause.

The estimated 20 percent of pregnant women who smoke during their pregnancies subject themselves and their fetuses and newborns to significant health risks, including miscarriage, stillbirth, pre-term delivery, low birth weight infants, and higher rates of infant mortality.

Smoking while pregnant has serious effects on the health of the baby. Untold adverse consequences affect the lives of those children and the people around them. A study from the Centers for Disease Control and Prevention (CDC) reports that smoking during pregnancy also increases the risk by 50 percent of having a child with mental retardation; this increased risk rises up to 85 percent among those who smoke a pack or more of cigarettes each day. The risk for Sudden Infant Death Syndrome (SIDS) increases among infants who are exposed to intra-uterine smoke and to second-hand smoke after pregnancy.

The younger an adolescent is when she begins to smoke, the more severe her nicotine addiction is likely to be. Additional health effects of smoking are: respiratory problems (and decreased physical fitness), dental problems (including periodontal degeneration), coronary artery disease, mental health effects (including nervousness, depression, more high-risk behavior, etc.), health-damaging behaviors, and other negative effects on quality of life (bad breath, wrinkled skin, stained teeth, and other negative effects that influence how she looks and feels).

We have preliminary evidence on how the smoker’s lifestyle affects the FIV™ menstrual cyclic profile captured by the Ovulona™.

Baseline cyclic profile of a healthy 30-years old non-smoker woman (who, as a baseline subject, is not taking any medication or contraception) shown here between two cyclic profiles of a smoking mother. The baseline profile was taken twice a day, morning and evening, and the AM and PM records show not only the reproducibility but also how the post-ovulation follicular waves develop between the morning and evening hours. The smoker’s consecutive profiles are similar to the baseline but exhibit significant differences. Cycle 4 record captured a delayed ovulation and short luteal phase. Cycle 5 shows also a short luteal phase, an abnormality (the luteal phase should be about 14 days long, give or take a day or two).

Image file URL: https://biozhena.wordpress.com/2012/02/21/smoking-affects-the-menstrual-cyclic-profile-as-captured-by-the-ovulona-which-might-help-with-smoking-cessation/non-baseline-profiles-flanking-baseline-subjects-ampm-profile-t/

We can imagine that a young woman trying to quit smoking may be helped in her effort by the Ovulona device. The Ovulona could be prospectively proffered for that purpose as a kind of biofeedback tool.

It is envisaged that tobacco interference with the fertility cycle will be recognized and accepted as a powerful motivator in the hard battle with the extremely strong addiction. “Is appearing ‘cool’ worth the resulting difficulty in getting pregnant, having a healthy baby?”

With public health education, the healthcare providers will be able to use the FIV cyclic profiles of the addicted patients to point out the affected features, and to monitor effects of treatment. “We really want to see this part of your cyclic profile to look more like this…”

The fallacy of ovulation calculators, calendars and circulating-hormone detectors

Don’t let them lead you by the nose with likely this and probable that! You need to know for sure.

When it comes to the crucial timing of ovulation, it is astonishing to see the fallacies and delusions propagated on the web – and that this includes even certain generally respected mainstream sources. How they declare, for example: If you’re trying to get pregnant, use this tool to find out when you likely ovulate and are most fertile.

Never mind that “most fertile” makes absolutely no sense because there is no such thing as a little fertile, more fertile and most fertile!

Ladies (and teenage young ladies included!), you either are fertile today or you are not: You either can conceive today or not.

It is either or.

You either are fertile today or you are not. It is not a little bit fertile, or more fertile, or most fertile. Like, you cannot be a little bit pregnant… you either are, or you are not.

Besides which, if you want to conceive a pregnancy, you must know with certainty that ovulation happens when you try to conceive – not merely that it is likely to happen. Unless you are reproductively ill or menopausal, it is always likely to happen at some point but the mere likelihood is not very helpful. Conception absolutely requires ovulation so that the released (ovulated) egg has a chance to be fertilized.

You must have a way of detecting ovulation at home and, based on that instrumentally recorded information, we will also help you with the Expected Date of Delivery (EDD), because that is how it works. Not the LMP (Last Menstrual Period) but the date of the conceptive ovulation — that’s the ovulation with which you became pregnant because your ovulated egg became fertilized. The date of ovulation is the date from which the EDD must be computed.

Ovulation caught on camera by Dr. Donnez – impressive but not a practical method of detecting ovulation

Fast forward to the principle that’s behind the take-home message of this post and that’s systematically arrived at by the end of this post:

Briefly: Tracking systemic effects (hormones in circulation) is not good enough for fertility status determination, especially if the purpose is pregnancy avoidance.

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To be blunt about the language of “likely ovulate” and “most fertile”: Such language simply reflects their inability to be definitive about it – and they therefore resort to guesstimating ovulation, calling it a calculation.

Numerous websites proffer their ovulation calculators when you search online for “ovulation”. A free, printable ovulation calendar and ovulation calculator to help you…, ovulation calculator can help you find the best time to conceive (as if there was some worse time when to conceive!), a calculator to generate your ovulation calendar and determine the best time…, our free Ovulation Calendar helps you predict your most fertile time of the month (ovulation) so that you can achieve pregnancy. Etc.

Notably and significantly, they do NOT promote this for natural (behavioral) pregnancy avoidance (birth control) but only as a tool for assisting conception – as if these were not the two sides of the same coin. They do not because they would get into trouble if they did.

A common approach relies on detecting, in a woman’s urine, the luteinizing hormone (LH) that typically surges on the ovulation day. The LH surge (sharp narrow peak in LH concentration) occurs a few hours before ovulation. Because that is really too late for anticipating ovulation, a related but more sophisticated fertility monitor additionally detects also a metabolite of estrogen, i.e., another hormone, which anticipates the LH surge by about a day.

The worst flaw of systemic hormone monitoring

Fundamentally the most serious detriment is the fact that ovulation as such is not detected by said fertility device or any other such available in the marketplace. Ovulation is merely assumed to occur some hours after the LH surge – but the surge of the LH hormone is merely a trigger signal sent by the brain to the ovary. It says, “ovary, let go of the ovum in our dominant follicle”, but it does not say that the ovary in fact did (or does).

This is a fundamental flaw because ovulation is known to fail to occur in approximately 20% of the follicles. Those follicles, triggered by the LH, undergo the cyclic event of follicle rupture but, despite the rupture, the egg does not come out – there is no ovulation.

In 20% of LH-triggered cases, the egg is not released so ovulation, as photographed here by Dr. Donnez, does not occur

Ovulation also fails to occur with another type of follicles, the so-called luteinized unruptured follicles. Yet, the LH surge can be seen in either case, and is therefore a false indicator.

Furthermore, when stress causes a delay of ovulation or absence of ovulation despite the LH surge signal (signal from the brain to the ovary), this cannot be detected and handled by the urinary hormone-based approach. As you can imagine, with our stressful lifestyle and environment, this is a very serious flaw that results in many disappointments. Our technology will make a big difference in managing the situation.

George Condo – Field of Figures sold for $450,000 at Skarstedt Gallery’s booth Published: June 14, 2011

Since, unlike our Ovulona™ Smart Sensor™ technology, their method depends on biochemical reagents and since the supply of the reagents is limited, their product’s user has to estimate on which day of her menstrual cycle she should start using the hormone-monitoring device when peeing into a cup. She does the estimating based on her previous menstrual cycle(s) as though the length and the timing of the present menstrual cycle were the same as in her previous cycle(s). Alas, that’s not so. Because of the variable lengths of successive cycles in most women, this is a weak feature in their design (even though they are getting away with it).

A key practical problem of the referenced 2-hormone device (the Clearblue® Fertility Monitor) is that the monitored urinary concentration of the estrogen metabolite E3G peaks only about 12 to 24 hours prior to the LH surge. This is not early enough to serve as a marker of the beginning of the fertile phase.

Fertile day 1 not identified

Their research or marketing literature may claim that “a sustained rise in E3G can be used to identify the start of the fertile phase”, referring to the slow gradual increase that eventually becomes the peak of E3G concentration. However, the idea to use an ill-defined rise – rather than the peak in the cyclic profile of the estrogen metabolite – is not a viable solution to the fertile window problem.

Even if the ill-defined E3G rise in the urine were correlated with a clearly defined stage of the egg development towards ovulation, a serious problem is that the rate of the E3G rise differs from cycle to cycle, as do the blood concentrations of E3G. The initially slow increase of the E3G concentration in the urine proceeds at different rates in different cycles, not only at different rates in different women. The E3G rise cannot be predictably associated with the beginning of the fertile period, and it cannot serve as a marker.

Schematic diagram of interaction between the LH and FSH hormone-generating glands in the brain (hypothalamus and pituitary) and those of the ovary (female gonad) generating estrogen and progesterone

The reasons are as follows:

1. Estrogen is known to have both stimulatory and inhibitory effects on LH secretion and, to be effective as a stimulant, it must rise to its peak levels (> 150 to 200 pg/ml) and must remain elevated for at least 36 hours [J. Hotchkiss and E. Knobil in E.Y. Adashi, J.A. Rock and Z. Rosenwaks, editors: Reproductive Endocrinology, Surgery and Technology, Lippincott-Raven Publishers, 1996].

In fact, the E3G rise indicates something else:

2. The E3G profile does not reflect the local interplay of estrogen with progesterone because it only reflects clearance of one of at least 10 metabolites of estrogen from peripheral blood circulation into the urine, after oxidative conversion in the liver.

Whatever the rate of this clearance process in the given woman in the given menstrual cycle, there are “local mechanisms due to which the quantification of ovarian steroids in peripheral blood or in urine is rendered interesting but of little value in predicting the genital end-organ effect” [C.J. Verco, in A.M. Siegler, editor: The Fallopian Tube. Basic Studies and Clinical Contributions, Futura Publishing Company, 1986].

The decades old problem is fundamental

This makes for the same basic flaw as that suffered by other monitors of peripheral hormones whether the hormone be progesterone (BBT monitoring) or estrogen (conductivity of saliva or of vaginal fluids).

Thus, the 2-hormone approach is in the end as inaccurate as the other LH-detecting techniques (the OPKs, Ovulation Predictor Kits). Therefore, like the other hormone monitoring methods, it cannot be approved and proffered for pregnancy avoidance since the failure rate would be unacceptably high. In fact, a law suit ensued in England, when the original developer company did sell the LH-and-estrogen monitor as a “contraceptive system”, and a number of unintended pregnancies resulted to the users.

See also below, under “Smart phone apps with the BBT?” the link about Natural Cycles – the app that got regulatory approval for contraception after their clinical trial with women who purchased the app because they believed they had “regular cycles” of constant cycle length.  Not surprisingly, problems and unwanted pregnancies ensued.

The fundamental point is this: The effects of the local and acute regulatory mechanisms (referenced under 2 just above) remain undetected by the old techniques that work with the peripheral biomarker variables.

Ovarian vein-to-artery exchange of steroids, prostaglandins and other bioactive substances is a local transfer mechanism which enables local regulation of ovarian, tubal and uterine functions. The local, as opposed to peripheral, blood concentrations of the steroid hormones are also believed to work with the innervation of the female genital tract (the cervix in particular).

The effects of these local and acute regulatory mechanisms remain undetected by the old so-called prior art techniques that work with peripheral biomarker variables. In contrast, our Ovulona™ detects them – via the cervix, the natural monitor of the female reproductive system.

Gustav Klimt – Medicine mural – Klimt’s primary subject was the female body

The flawed assumption of similar timing of menstrual cyclic events from one cycle to another has been a problem for the BBT and the BBT thermometers. Since the late sixties, the microprocessor technology has been applied by a number of people to the well-tried basal body temperature [BBT] approach to family planning that was originally hoped to work for pregnancy avoidance.

Smart phone apps with the BBT?

The BBT approach is no longer recognized as medically valid even if it may be acceptable to some of the older physicians, and to the younger buyers of an expensive microcomputerized BBT monitor offered from Europe and/or to the users of the more recent smart phone apps based on BBT monitoring.

This is because the so-called basal body temperature is a systemic variable that reflects, among other things, progesterone rise in peripheral blood after ovulation, usually one or two days later.  It is a very indirect and non-specific biomarker. Even though in some women in some cycles a little-understood dip in the temperature graph may apparently be observed one day before the temperature rise, it is clear that the BBT method is of little value due to its lack of predictive capability and due to its fundamental unreliability. The BBT-rise data is known to have a large error bar since the rise can occur from 3 days before to 3 days after ovulation.

For a more detailed critique of the BBT monitoring approach and a rebuttal of a particular European product, peruse Critique of BBT monitoring – DuoFertility rebuttal. Also read a note on 3 things that differentiate our technique from the smartphone apps and particularly the most recent, Natural Cycles .

Briefly: Tracking systemic effects (hormones in circulation) is not good enough for fertility status determination, especially if the purpose is pregnancy avoidance.

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Purveyors of the old “prior art” technologies get away with it because of the high demand for any help with the serious and growing problem of sub-fertility, more commonly called trying-to-conceive or difficult getting pregnant. When the purveyors publish anecdotal evidence of “efficacy” in the form of thank-you letters from women who did achieve pregnancy, we should keep in mind that the women received help in focusing on trying to hit the fertile period regardless of whether the given technology actually did work or not.

If any of the “prior art” did work reliably, it would be used as a pregnancy-avoidance tool, which is not the case (with the one exception noted above, a reservation included suggesting that only women with self-assessed regular cycles opted to buy the BBT-and-calendar based app with its 11 “unsafe” days offered to the user instead of the true fertile window).

Venus, Cupid, Folly, and Time (also called An Allegory of Venus and Cupid and A Triumph of Venus) is an allegorical painting by the Florentine artist Agnolo Bronzino – circa 1545.  The bearded bald figure to the upper right is believed to be Time…

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Now go see about “Instant detection of pregnancy and of Early Pregnancy Loss, EPL – the adversary of Trying To Conceive, TTC – especially after age 25″ at https://biozhena.wordpress.com/2010/11/11/instant-detection-of-pregnancy-and-of-early-pregnancy-loss-epl-the-adversary-of-trying-to-conceive-ttc-especially-after-age-25/

And should you be an investor and/or wish to find out more, check out  Home Page of bioZhena’s Weblog

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