Posts Tagged ‘folliculogenesis’

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

August 2, 2016

Warhol, Andy, Dollar Sign, 1981Some time back, I published here a blog post titled “The Ovulona is not another ovulation kit, my dear” in response to a Jennifer K. who had written: How is this different from the other ovulation kits on the market today? It seems very similar to products I have seen before. At the time, my blog posts were addressed to all the fertility info-seeking Jennifers (and Jeffreys, too) out there in the social networks but not particularly to the women’s healthcare technology investors.

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.)

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.

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)

FVS compared with MVSClick 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.

‘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. Indisputably conservative.

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

Oh joy  Found on poodlefuzz.tumblr.com

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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 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 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

 pregnant 2

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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.

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

Boatswain is piloting the Eagle to the dock

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

And for Investors – PPM at https://www.equitynet.com/profile.aspx

Might check out first  Home Page of bioZhena’s Weblog

How baby-making late in life evolved into subfertility and infertility, difficult conception, too long TTC

December 28, 2012

Way back, in the pre-contraceptive Pill days, the difficulty to become pregnant was not a widespread phenomenon, and mums were  younger than many are nowadays. If you want to see graphical proof of how the phenomenon came about in the previous century, review the attached paper Google evidence of increasing prevalence of subfertility. Should you not be a subfertility or infertility sufferer, and therefore not familiar with the acronym, TTC stands for Trying To Conceive.

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

In 1940, births to mothers over 29 years old (30 to 49) were apparently almost as numerous as births to mums of the optimal fertility age 20-24: The ratio of 30-49 years old to the optimal-age group was 0.91 [here referred to as ratio a) =  data for 30–34 plus 35–39 plus 40–44 plus 45–49, this sum divided by data for 20–24], and the number of births in the most fertile age group of mums represented 31% of all births in the U.S.

In case you did not check out the above-linked attachment https://biozhena.files.wordpress.com/2012/12/google-evidence-of-increasing-prevalence-of-subfertility.pdf : The high number of 1940 births to older mothers [high ratio a)] is not so surprising in view of the growing number of books on subfertility and infertility in the 1940s, as seen in the respective Google Ngrams shown here and discussed in the attached PDF paper.

Ngram 3: infertility and contraception

Ngram 3: infertility and contraception

In the present analysis of the historical birth rates, the age group of 25-29 is considered kind of neutral (neither optimal nor too old) whereas the 30-34 years old group is included among the too old ages for optimal fertility. This inclusion could be disputed – if we did not face the subfertility/infertility phenomenon, in which age is a significant factor. In any case, excluding the 30-34 age group from the aged-motherhood definition only delays the trend reversal – observed below in 1980 – by a decade.

I interject here a citation from the post referenced and linked at the end of this post, so that you’ll be well aware of the link between conception difficulties and advancing age, and of the adverse effect of the use of the Pill.

QUOTE: 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- and 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. … Advanced age of the would-be Mum works against her on account of the Mother Nature’s Probabilistic Rules and Regulations of Baby-Making… END QUOTE.

An obgyn’s article on female subfertility in the Lancet invokes “two main factors that determine subfertility: duration of childlessness and age of the woman”. It is not likely that an obgyn would be as critical of the Pill as yours truly, although there have been exceptions. No further comment on this is needed or offered in this blog post. Instead, I share that another medical article from Britain reported that “the incidence of infertility was 0.9 couples per 1000 general population. The average age of women was 31 years, and the average time attempting conception was 18 months… At 12 months, 27% of all couples in the study achieved a pregnancy spontaneously and a further 9% with treatment.”

Here are the 1940 US birth statistics data from the referenced infoplease.com source:

Year

Total

Under 15

15–19

20–24

25–29

30–34

35–39

40–44

45–49

1940

2,558,647

3,865

332,667

799,537

693,268

431,468

222,015

68,269

7,558

And this is the calculation for the present analysis of the data:

a) 729,310/799,537 = 0.912

(ratio a is the sum of births to age groups from age 30 to age 49 divided by births to age group 20 – 24)

b) 799,537/2,558,647 =  0.312

(ratio b is births to age group 20 – 24 divided by total births in 1940)

By 1950 and 1960, the trend was good because ratio a) declined from 0.91 to 0.86 and then to 0.80 while the number of optimally aged young mothers rose slightly to 32% and then to 33.5%. These pre-Pill years were good years from this perspective, and the trend continued – even after the contraceptive Pill was introduced (in the 1960s), at least initially.

In 1970, there was a drop in the total number of births from the total of 1960 (4,257,850 births) and a dramatic drop in the number of births by aged mothers [ratio a) was 0.47] – and the births by the most fertile age group were up to 38% of all births. As though the contraceptive Pill worked in this sense (but only if we do not look at the significantly increased births by underage girls, especially the under 15)… Here is the 1970 data from the above source:

Year

Total

Under 15

15–19

20–24

25–29

30–34

35–39

40–44

45–49

1970

3,731,386

11,752

644,708

1,418,874

994,904

427,806

180,244

49,952

3,146

Unfortunately, in 1980 – that’s some 20 years after the Pill was introduced – the trend started to reverse while the total births continued to drop (and underage births dropped, too): Ratio a) of the number of aged mothers’ births to the most fertile age group’s births rose to 0.58 and births by the most fertile 20-24 year old mums represented now only 34% of total US births. The bad trend toward older-age motherhood continued.

By 1990, there were even more births to aging mothers than births to the most fertile age group, with ratio a) standing at 1.15 and the number of births to mothers of the optimal age group having dropped to a mere 26%.

The bad trend continued so that in 2000 advanced-age mothers exceeded the optimal-age group with ratio a) at 1.45, and with the optimally aged mums at 25% of total births. The trend continued further so that in 2009 advanced-age mothers exceeded the optimally aged mums by a factor of 1.53 [= ratio a)] and the optimal age group’s births dropped to 24% of total births. Data for 2009 are the most recent available data.

Tamara de Lempicka Quattrocento, 1937

Tamara de Lempicka Quattrocento, 1937

Is the difference between way back and now the reason for one other elevated readership statistic here on bioZhena’s Weblog? It is intriguing to see that during the months of the highest numbers of US births/deliveries (late summer and autumn, well before the year-end Holiday Season), a highly viewed post this year was the one published around the time of Mother’s Day: 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/ Say thank you to the social and medical advances of the twentieth century – primarily those of chemical birth control, the Pill.

What do you think of all this?

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

May 28, 2012

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, 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.

First, here is a summary of my 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 this summary with the full abstracts and references shown below.

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.

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

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.

Steroids

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

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.

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

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

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”. Or is it the other Uncle that you are barbecuing with in Omaha, this Memorial Day?

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

February 21, 2012

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.

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

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™.

Non-baseline profiles flanking baseline subject's AM&PM profile

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…”

Stress and fertility: How stress affects the inherently narrow fertile window

February 2, 2012

This blog post appears as the third result in Google search on “bioZhena” (without the quote marks). The complete title is:

Stress and fertility

How stress affects the inherently narrow fertile window

To read the whole post, click on either of the antique-book images or on Reblogged from bioZhena’s Weblog:

Before you go there, here is a little update. New research into stress and fertility was published since I wrote the blog post in December 2007, and here is a summary of an article titled “Stress puts double whammy on reproductive system, fertility” (see http://esciencenews.com/articles/2009/06/15/stress.puts.double.whammy.reproductive.system.fertility ).

 

QUOTE: The new research shows that stress also increases brain levels of a reproductive hormone named gonadotropin-inhibitory hormone, or GnIH, discovered nine years ago in birds and known to be present in humans and other mammals. This small protein hormone, a so-called RFamide-related peptide (RFRP), puts the brakes on reproduction by directly inhibiting GnRH.

The common thread appears to be the glucocorticoid stress hormones, which not only suppress GnRH but boost the suppressor GnIH – a double whammy for the reproductive system. END QUOTE

 

Unlike any other fertility monitoring technology, bioZhena’s Ovulona™ is a Smart Sensor™ in vivo monitor of folliculogenesis. Unlike any other fertility monitor, the Ovulona is basically involved with the always-present stress responses – through monitoring certain end-organ effects on folliculogenesis. The other techniques monitor only this or that circulating hormone – not good enough. The end-organ effect(s) is what counts.

 

Again, to read the whole post, click on either of the antique-book images or on Reblogged from bioZhena’s Weblog

 

For a 2012 update go to 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.)

bioZhena's Weblog

How stress affects the inherently narrow fertile window

Stress can do unwanted things to a woman and her menstrual cycle. In a nutshell, stress can make a woman completely infertile in this menstrual cycle (e.g., LPD, see below), or it can change the position of her fertile window (the time of ovulation included) within the menstrual cycle. Any of this can cause problems and lead to more stress…

The medical term is stress response, and it refers to the overall reaction of the organism to any adverse stimulus, whether it be of physical, mental or emotional kind, internal or external. The purpose is to adapt to challenge, and this goes on all the time. (C’est la vie! Real life is a never-ending series of stress responses.) Should the compensating reaction of the organism be inadequate or inappropriate, a pathological disorder may result.

The HPA axis, the immune system and the…

View original post 1,035 more words

Much in women’s health revolves around folliculogenesis – from teen age to peri-menopause

November 30, 2011

In this article I sketch for you the usefulness of the Ovulona™ Smart Sensor™ throughout a woman’s life, with particular attention paid to the extremes of the reproductive lifespan.

We outline the significance of the cervical tissue biosensor for a woman’s health management from adolescence (the teen years) to peri-menopause. This schematic diagram is a pictorial synopsis of the multi-purpose utility of the Ovulona throughout most of a woman’s lifetime.

Ovulona throughout a woman's life

As you recall from prior posts on this blog, FIV™ stands for FOLLICULOGENESIS IN VIVO™, which translates as the sequence of menstrual cyclic records that will be captured and stored (automatically saved) in the Ovulona during normal use by a woman at home. The data is available for transfer to healthcare providers’ Ovulograph™ for medical uses during the reproductive years.

The reproductive age is officially defined as 14 to 44 but we’d encourage, for health reasons, to chop off a few years at both ends from the actual reproductive (high end) or sex-exploration activities (low end). When folliculogenesis – i.e. menstrual cycling – ceases in menopause, hormone therapy and cervical tissue health screening are the two components of menopause and post-menopause health management, to which the Ovulona is applicable.

In this article, I address very briefly (tweetingly!) the two “boundary conditions” of said reproductive years.

I’ll deal with the young boundary condition, i.e. adolescence or teen age, in the style popular nowadays especially at that stage of life . That is, I let speak a few tweets, mostly from http://topsy.com/biozhena.wordpress.com/2009/03/12/far-more-than-a-tool-for-reproductive-management/ .

When you look at the tweetingly referenced papers (click the short URLs below), you will see how the teen cramp sufferer needs our Ovulona. That’s because she must take the anti-inflammatory medication before the ovulation-linked pain hits, otherwise the med would not work. She – or is it you? – must be able to anticipate ovulation. You need the Ovulona. The timing is crucial, similar to the right timing for conception purposes… (Recommended reading: http://endometriosis.org/treatments/painkillers/ = http://to.ly/6ZsS in the #NSAIDs tweet below).

If it’s menstrual bleeding (not ovulation) that pains you, the Ovulona will tell you when you expect that – whether it is ovulation + 14 days or, probably more likely at this young age, ovulation + irregular. You’ll then see on the display your recorded min and max, with respective probabilities the more accurate the longer you’ve used the Ovulona. That’s this app’s meaning of Smart Sensor™ for you! (And that is because we don’t track just this or that hormone in your pee! Or your BBT, or your signs…)

As for the STD screening aspect of those young years, indicated in the pictorial synopsis above, I refer you to the recent posts in this blog; and the sex ed use of the Ovulona – or rather its recorded data and their discussions in classes – is self-explanatory.

But then there is the subject of chemical contraception, the Pill. So, here, a couple of tweets from http://topsy.com/biozhena.wordpress.com/2010/06/27/about-atrophy-reproductive-aging-and-how-it’s-really-not-nice-to-fool-mother-nature–or-with/?utm_source=topsy_module

A teenage girl has a #dilemma With the #Pill she brings on herself a significantly earlier #menopause & likely difficulty to #conceive when desired http://to.ly/5f2W

#Menstrual #cramps are bad but don’t allow them – by taking the #Pill – to cause you the much worse #pain of TTC #infertility http://to.ly/5f2W    [TTC = Trying To Conceive. That’s the phrase and acronym used by people who have difficulty getting pregnant.]

http://to.ly/5f2W Even with just 3-15 months of #contraceptive #pill use you suffer greater loss of S crypt cells than can be replaced. Then hard TTC is likely   [S crypts are part of the microscopic structure of the cervical epithelium, of the tissues.]

Here now are those few tweets referring to dysmenorrhea, the menstrual pain which causes so much suffering and so many lost hours at school and/or at work. In this day and age!

#NSAIDs against #endometriosis pain http://to.ly/6ZsS Since you must take the meds BEFORE expected #cramps you need our Ovulona tool to anticipate ovulation http://to.ly/MJS [NSAIDs = Non-Steroidal Anti-Inflammatory Drugs]

@bioZhena/fertility    http://to.ly/MJS Why most girls get cramps What goes on there Why & what’s PCOS See it with Ovulona [Obese girls tend to grow into women with PCOS = Poly Cystic Ovary Syndrome, the cause of major killer diseases, and often causing infertility.]

Folliculogenesis #InVivo for Why Do Most Girls Suffer With #dysmenorrhea #cramps http://to.ly/MJS #womenshealth #diagnostic #medicaldevice

Ovulona for etiology & management of  #dysmenorrhea Why do teen girls suffer with #crampshttp://to.ly/MJS #pharma #medtech #medicaldevice [etiology = the cause or origin of a disease]

Re: etiology of adolescent #dysmenorrhea Prostaglandin theory & treatment known since the 1980s Why are period cramps still so bad?

I leave you and this “boundary condition for Ovulona’s use” with two Google Insights graphs. Look here how the worldwide interest level in the subject of period cramps has been increasing since 2004.

Period cramps worldwide searches from 2004 by Google Insights

Period cramps worldwide searches from 2004 by Google Insights

Don’t ask me why the recorded public interest is emanating from those particular English-speaking countries and not from numerous others, and look for details at http://www.google.com/insights/search/#cat=0-45&q=period%20cramps&cmpt=q (you can change the selected parameters and observe the effect of the changes).

I merely note the periodicity developing in the data in recent years on top of the clear upward trend, the periodicity indicative of highest interest in summertime (such as in July 2011)…

This is, of course, the same in the next graph, where I added dysmenorrhea (red) for comparison. That’s a difficult word, so it is not as much searched on as the colloquial cramps – except for, if you look closely, in (Southeast)Asia.

Period cramps & dysmenorrhea worldwide searches since 2004 by Google Insights

I’ll now use one more tweet to segue into the other end of the span of reproductive years.

#estrogen can be a good medication but we need #personalizedmedicine tools We must measure & titrate #hormone uptake http://t.co/CeCsWgn

The following illustration shows that we at bioZhena have the technology with which to do that, i.e. a tool with which to adjust treatment to suit a given female patient.

The illustration is a graph of the effects of estrogen and progesterone monitored with our technology in an ovariectomized pig. Ovariectomy is the removal of the ovaries. It is the animal equivalent of surgical hysterectomy, which causes surgical menopause since the reproductive system no longer produces said sex hormones, the sex steroids estrogen and progesterone.

In the illustrated experiment, the steroids were later given to the animal (after recovery from surgery), and the result was that progesterone drove the sensor signal down versus estrogen drove it up (as seen in FIG. 5 below, excerpted from our patent portfolio). This is a useful finding, for example for monitoring the effects of hormone replacement therapy (HRT). 

Graph of estrogen and progestagen effects on porcine cervix

Graph of estrogen and progestagen effects on porcine cervix

We also have the proof of the concept generated by a menopausal woman, using a Premarin treatment in that experiment (Premarin is an estrogen medication used for treating the symptoms of menopause including hot flashes, vaginal dryness, etc.). The data was used in another patent in our portfolio.

Background on menopause, HRT and bioZhena can be found in the early blog post at https://biozhena.wordpress.com/2007/12/18/menopause-hrt-and-biozhena/ .

Experts advocate that women in their 30s and 40s should look at menopause now. Health maintenance depends on diagnostic tools. We propose that the preparation for menopause be done – in a simple quick daily routine – by systematically monitoring the Ovulona menstrual cyclic profile, and how it changes over the years. How it responds to pregnancy and birth, to things like diet, exercise, various ills, various medications, stress… in the particular woman user, not some statistical average. For evidence-based personalized health care.

That’s the broader meaning and the purpose of the folliculogenesis cyclic profile generated by the Ovulona. It’s not merely (“merely”!) for helping to get pregnant or for avoiding pregnancy without chemicals, as is illustrated and described in “Pregnancy and birth control how-to by bioZhena” at this Photobucket site. In the third graphic, on this page, see the follicular waves that relate to follicular age, i.e. how fast is menopause approaching, after pregnancies were successfully achieved and then regulated in this Ovulona-guided manner.

This is because the cervix monitors the physiological inputs after conception and after pregnancy just like it does the monitoring before fertilization and before birth. We pick up the diagnostically useful information from this key female organ. We speak of end organ effects.

For a still broader perspective, including symptometric monitoring correlated with folliculogenesis, go to “Far more than a tool for reproductive management”.

STOP PRESS

And after all that, go and check out the 2012 post “The fallacy of ovulation calculators, calendars and circulating-hormone detectors” at https://biozhena.wordpress.com/2012/02/13/the-fallacy-of-ovulation-calculators-calendars-and-circulating-hormone-detectors/

Instant detection of pregnancy and of Early Pregnancy Loss, EPL – the adversary of Trying To Conceive, TTC – especially after age 25

November 11, 2010

Early Pregnancy Loss is also known as #stillbirth or #miscarriage, or Early Embryonic Mortality (EEM), and the Ovulona™ is a tool of evidence-based personalized medicine.

After the optimum fertility age of the early twenties, achieving motherhood gets more difficult. It becomes even more essential than before to know your three fertile days, during which – and only during which – conception can occur.

The simple basic principle is: Fertility status detection must be easy and reliable. PLUS early pregnancy detection is really important, and it should be built-in, an integral part of the conception-aiding tool.

Why? Because:

1) early in pregnancy the conceived baby would be harmed by some of the medications taken by the woman, e.g. by a psychiatric medication with teratogenic effect (harmful to the fetus, causing a congenital disorder);

and 2) because of the annual 600,000 miscarriages – per CDC statistics – out of the 6 million US births, which means that at least some 10% of pregnancies are lost to early pregnancy loss (EPL), miscarriage, stillbirth.

Many EPLs go unnoticed. The EPL is a part of the TTC [Trying To Conceive] or subfertility/infertility problem. Our Ovulona monitor of FOLLICULOGENESIS IN VIVO™ is the prospective solution for managing the problem.

The Ovulona™ detects the 3 fertile days for conception, and it will also automatically detect pregnancy immediately upon conception. Similar to early pregnancy loss — its detection is the inverse of pregnancy detection, which both involve the follicular waves. Like this:

Follicular waves disappear = pregnancy detected

versus

waves reappear in early pregnancy =  early pregnancy loss detected.

Furthermore, the cyclic profile data captured by the Ovulona can be used by your healthcare provider to assess what is going on, and provide more effective help.

DIFFICULT USE OF EXISTING OPKs [Ovulation Prediction Kits] is shown in the following tweet by a @WannaBeMom: “1st month using opk. Do the lines usually start light and then get darker day by day or do they ever go back & forth b4 ovulation?”

Our electronic device will take the WannaBeMoms into a different world of baby-making. See  http://s755.photobucket.com/user/vaclavkirsner/library/Second%20album/Pregnancy%20and%20birth%20control%20how-to%20by%20bioZhena?sort=2&page=1 = a pictorial “Pregnancy and birth control how-to by bioZhena”.

Honey is Sweeter than Blood by Salavador Dali, 1941

Honey is Sweeter than Blood by Salavador Dali, 1941

For a woman in her 30s who’s had a miscarriage or even two or three, “any delay in attempting conception could further decrease the chances of a healthy baby”, says CNN reporting on a medical study, http://www.cnn.com/2010/HEALTH/08/05/miscarriage.try.again.asap/ .

Study: Women who conceive within six months of miscarriage reduce risk of another.”

November 2016 review and meta-analysis (data on more than a million women): “With an Inter Pregnancy Interval of less than 6 months, the overall risk of further miscarriage and preterm delivery  were significantly reduced.”

These are fundamental principles.

And another principle, not brought up by the CNN or by the study itself, is that a tool for monitoring the early stage of pregnancy for EPL is most desirable. We’d say, mandatory. The Ovulona device monitors (or tracks the process of) folliculogenesis in vivo, which includes the follicular waves that occur after ovulation. The waves disappear upon conception because the reproductive system does not go into another menstrual cycle – it’s pregnant.

In case of EPL, Early Pregnancy Loss (miscarriage), the waves will come back. Early Pregnancy Loss, or Early Embryonic Mortality, is quite a common sad experience of many of us.

The essential point made here is that the woman’s and her physician’s decisions should be guided by the folliculogenesis cyclic profile (and/or its distortion due to distress of any kind). The woman and her doctor should not make decisions or pass recommendations working in the dark, and the data, on which any decision should be based, must be personal to the given patient.

That’s what the Ovulona from bioZhena is for. Personalized medicine. Evidence based medicine. Should you be new to this, https://biozhena.wordpress.com/about/ is an introduction.

Automatic pregnancy detection is inherent  in the Folliculogenesis In Vivo™ cyclic profile

Automatic pregnancy detection is inherent in the Folliculogenesis In Vivo™ cyclic profile (follicular waves disappear).

This is a screen shot of one of my narrated slides about “what’s going on here”, and you can view (and hear) the slide at https://biozhena.files.wordpress.com/2015/07/single-slide-unprecedented-wealth-of-info-narrated.pps.

Note specifically that: The follicular waves, which occur after ovulation [when the body prepares for the next menstrual cycle], cannot remain in place after fertilization succeeds and conception takes place [because the post-ovulation regime change is even more profound]. That is the principle of instant detection of pregnancy. As opposed to the waiting for the HPT [Home Pregnancy Test] result.

HCG or Human Chorionic Gonadotropin laboratory signature

HCG or Human Chorionic Gonadotropin laboratory signature of the biomarker – detected in a pregnant woman’s urine about 2 weeks into her pregnancy by a HPT home-use urine test – as a color change (into which color the HPT reduces the illustrated complex lab signature)

Should the conceptus [product of conception, early embryo] be lost to EEM, Early Embryonic Mortality (miscarriage), the follicular waves come back to be seen by the Ovulona. That’s the principle of early detection of the miscarriage, and of detecting the return of the non-pregnant condition.

Trying to conceive again should be based on the personal FIV™ [FOLLICULOGENESIS IN VIVO] cyclic profile data generated by the patient, that is, by the woman trying to have a baby. This is a principle of evidence-based medicine. Personalized medicine.

Entre Les Trous De La Memoire by Appia

The Ovulona is intended to help people such as those writing in a forum as follows:

My partner and i started trying for a baby in jan And Concieved in the first month. Unfortunately in march at 8 weeks I had a miscarriage. We have been trying since with no luck. Could something be wrong. Please help this is really getting me down. http://www.netdoctor.co.uk/interactive/discussion/viewtopic.php?t=57881&f=5

We got pregnant the first cycle with both my ds and dd. I am most likely moving to cycle #11 with this baby. We did conceive on the second cycle of trying with baby #3 but we miscarried a week later. Nothing since then. I’m not sure why this time is taking so much longer. http://www.mothering.com/discussions/showthread.php?p=16029816

Can anyone advise? My daughter has been trying to get pregnant for several years. Her husband is fine. My daughter has now been asked to go for a scan which scared the life out of me (you automatically think something is horribly wrong). Can someone tell me what the scan is about – what sort of scan is it? http://www.netdoctor.co.uk/interactive/discussion/viewtopic.php?t=31528&f=5

The information contained in the folliculogenesis cyclic profile, as illustrated in the slide captured above, is meaningful and can help the healthcare provider to answer questions such as these.

Trying to conceive, #ttc, or the frustration of sub-fertility & infertility

November 9, 2010

Existing approaches to TTC, Trying To Conceive, are not satisfactory – and cannot be, without FOLLICULOGENESIS IN VIVO™

Here is the premise: To #conceive a #pregnancy the couple must absolutely do their #TTC in the woman’s #fertile time, which is a window of 3 days: https://biozhena.wordpress.com/2010/05/25/difficult-conception-tied-to-pregnancy-complications-addressed/ . The unspoken corollary is that advancing age does not help, and neither do things that pollute our life, that is all those various stressors.

Besides which, you need to know not only when your ovulation is approaching but also that it actually occurs. No guessing, no mere assuming that it does, or that it did.

Human ovulation caught on camera by Dr Donnez

Human ovulation caught on camera by Dr Donnez

This photo of the ovulation event is unique, and it clearly cannot be the answer to the necessity of knowing that ovulation occurs in the menstrual cycle of interest to you. Also unique is that the Ovulona™ will do the determination of ovulation for you automatically – in your hands, at your convenience, with no discomfort. It’s one part of the FOLLICULOGENESIS IN VIVO™ simple self-monitoring procedure with the Ovulona™. In doing so, you’ll gather and automatically store in the device data of diagnostic significance to your healthcare providers. Your physician’s decisions should be guided by the folliculogenesis cyclic profile. Yours, too.

Here now, how #ttc people need our Ovulona: Disgusted with peeing on a stick, writes stressed out, frustrated, messed up @socalledttclife: “On to IUI #4 we go” [IUI = Intra Uterine Insemination procedure], http://ow.ly/351yf .

She blogs: “…Progesterone supps suck. No, really, Crinone is now numero uno on my most hated list right there behind peeing on a stick and betas. It totally MESSED with my head this cycle. It made me crampy, it gave me headaches, it delayed my period—ALL of the things that are usually early pregnancy symptoms. Damn you, Crinone!”

This is one example and one reason why a month ago the following tweeting dialog took place: RT @resolveorg What’s the one thing you wished the public knew about #infertility?

bioZhena’s answer = Before #fertility #drugs, try right timing http://to.ly/5dUR . Definitely! Read on.

Quite apart from the fact that even the artificial reproductive procedures such as said IUI have to be performed at the right time in the patient’s cycle to have a chance succeeding. Before undergoing the “heroic procedures” of Artificial Reproductive Technologies [ARTs], explore the normal natural approach, and – naturally – you need a reliable timing tool to know when exactly your 3-day fertile window occurs. Good thing you are still this side of 35, although it would be much better if you were this side of 25. Or 30, at least. But that’s water under the bridge… unfortunately.

Water under the bridge… How many bridges?

Water under the bridge… How many bridges?

Per Google Alert, Today’s #TTC Trying To #Conceive forum has 4 results that are symptomatic of the TTC world – and how that world needs our Ovulona diagnostic tool with essential folliculogenesis data for the physicians:

1. Conceiving in our 20s http://www.mothering.com/discussions/showthread.php?p=16007861

2. healthy excersise while TTC – TTC- Trying to conceive Group so im a gymaholic… Before I go to my GP again with yet another silly question, what do you girls think, with your experience and knowledge, about my standard work out ‘plan’ below? Is this too much while TTC? … Thoughts? Please don’t make me not do it 😦

social.kidspot.com.au/topic.php?topic_id=8490

3. First time TTC with clomid and really nervous, any suggestions?? Forum · PCOS Treatments and Conditions · Infertility and Trying to Conceive; First time TTC with clomid and really nervous, any suggestions? …
www.soulcysters.net/showthread.php?t=317229&page=2

4. Pregnancy Forum UK : UK Pregnancy Forum Parenting and Baby forum …
hey all i had a positive opk on fri am but this morning days later had twinges on left hand side which feel like op is it possible that i have only just …
178.19.113.123/viewtopic.php?f=8&t=114228&view…

#PCOS patients should monitor folliculogenesis & the effects of any treatment on it. See http://to.ly/MJU , and for what it is go to http://to.ly/757m , and see how an obgyn physician related to the technology even early on when it was still in a rather crude prototype form: http://to.ly/vG0 .

As we expressed earlier in this blog:

It is advisable – and safer – to go about TTC, Trying To Conceive, without the use of chemicals, especially man-made chemicals, and note that herbal preparations are chemicals too. Monitoring (measuring) the effects of anything you ingest is basically a must, if you do not play “Russian roulette” with yourself, your offspring, your family.

#Obese peri-pubertal girls may have hyperandrogenemia which can be forerunner of #PCOS: http://to.ly/6PrK .

Not all #women with #PCOS have difficulty achieving #pregnancy, but anovulation is a common problem: http://to.ly/5mjs .

#PCOS problems are more about #prevention of diseases due to PCOS = #endometrial #cancer #diabetes #heart disease #strokes: http://to.ly/5mjs . Per @JoshGitalis : Insulin resistance is an underlying biochem. imbalance in not only type 2 #diabetes, but #CVD, #hypertension, #PCOS, and colon/breast cancer.

RT @kevinmd Too many young children are medicated with powerful #drugs http://goo.gl/fb/xXu5q – Too many #women too. Will this ever be seen as abuse?

Durer, Albrecht - The Temptation Of The Idler (or The Dream Of The Doctor)

Durer, Albrecht – The Temptation Of The Idler (or The Dream Of The Doctor)

Difficult #conception is tied to #pregnancy complications: http://to.ly/4Fih #fertility #TTC #conceive #womenshealth . Read also: http://to.ly/6ahN .

#Natural vs. #Clomid in Dr. Randine Lewis: From #Infertility to Motherhood, http://to.ly/60v6 . Wrote the #medical doctor:

“I was experiencing hormonal problems. My joints ached, I had lower back and knee pain, I had to urinate frequently, I had night sweats, I was experiencing hair loss and my periods were extremely irregular and sometimes nonexistent.

A medical work-up revealed my estrogen and progesterone levels were alarmingly low, resulting in my inability to conceive. The doctor recommended that I take Clomid, a drug designed to hyperstimulate a woman’s ovaries to produce more eggs, thus increasing the chances of pregnancy. This advice seemed wrong to me; what about the underlying problem? Was it not unwise to hyperstimulate my ovaries when the problem obviously resided in my whole hormonal system?”

Now, put that in context with More About Clomid, Serophene, Clomiphene citrate or Clomifene, http://to.ly/5dUr . Why popping pills is not the best.

Is #ovulation enough to #conceive? http://to.ly/4Fih . Not really. You have to satisfy 4 factors, 4 prerequisites:

1. good health,

2. right insemination timing,

3. fertilization works,

4. embryo lives, is not lost to early embryonic mortality.

#Stress can do unwanted things to #women & #menstrual cycles: http://to.ly/yBk . Check this out. Sub-fertility can result.

30% of women or couples cannot get pregnant

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. See why.

STOP PRESS

And now, for a more explicit and detailed info, go to the 2012 post “The fallacy of ovulation calculators, calendars and circulating-hormone detectors” at https://biozhena.wordpress.com/2012/02/13/the-fallacy-of-ovulation-calculators-calendars-and-circulating-hormone-detectors/

How follicular waves will be used for early detection of pregnancy, and for early detection of miscarriage, EPL – to TTC again asap

August 25, 2010

In this post we talk again about the feature introduced in an earlier post, https://biozhena.wordpress.com/2010/01/10/about-the-added-bonus-of-folliculogenesis-monitoring-automatic-pregnancy-detection .

This time we focus on the importance of the utilization of the follicular waves not only for practically instant pregnancy detection, but also for a similarly early detection of miscarriage or early pregnancy loss (EPL, also known as spontaneous abortion, SAB). Refer to Early Pregnancy Loss,  http://emedicine.medscape.com/article/260495-overview . Note: Chief Editor is Professor Lee P. Shulman, MD, FACOG – one of bioZhena Corporation’s Board of Medical Advisors.

Sonography scene. Some contrast vis-à-vis the Ovulona™!

Sonography scene.   Some contrast vis-à-vis the home-use Ovulona™!

Excerpted from said Medscape overview: Early pregnancy loss is unfortunately the most common complication of human gestation, occurring in at least 75% of all women trying to conceive. Most of these losses are unrecognized and occur before or with the next expected menses. Of those that are recognized, 15-20% are spontaneous abortions (SABs) or ectopic pregnancies diagnosed after the pregnancy is clinically recognized.

The incidence of spontaneous miscarriage is 10-15%, whereas the rate of recurrent miscarriage is 3-5%. Approximately 5% of couples trying to conceive have 2 consecutive miscarriages, and approximately 1% of couples have 3 or more consecutive losses.

Early pregnancy loss is defined as the termination of pregnancy before 20 weeks’ gestation or with a fetal weight of below 500 g. An article in http://www.cnn.com/2010/HEALTH/08/05/miscarriage.try.again.asap/ summarized the conclusion that “any delay in attempting conception could further decrease the chances of a healthy baby”.

This is a fundamental concept. Further they write, with reference to the original BMJ publication, “Study: Women who conceive within six months of miscarriage reduce risk of another… The women who conceived within six months also had better overall outcomes. They were about 10 percent less likely to have a C-section or a preterm delivery, and about 15 percent less likely to have a baby of low birth weight than the women who waited up to a year.”

This is a highly suggestive conclusion, implying the need to know as soon as possible. The sooner the better for attaining happiness.

Angelo Bronzino - Allegory_of_Happiness, 1564

Angelo Bronzino – Allegory_of_Happiness, 1564

Another fundamental principle, not brought up by CNN or by the study itself, is that a tool for automatic monitoring of the early stage of pregnancy to watch out for EEM [Early Embryonic Mortality] is desirable, to put it mildly. Our Ovulona™ device is perfect for that. The Ovulona monitors folliculogenesis in vivo, which includes the follicular waves occurring after ovulation. The waves disappear upon conception (the pregnant system does not go preparing for another menstrual cycle, which the follicular waves signify).

The follicular waves disappear as soon as conception takes place and the woman is in early stages of pregnancy. In case of miscarriage, the waves will come back. The point made here is that the woman’s and her obgyn’s decisions about trying for pregnancy again should be guided by diagnostic data. The data on which any decision should be based must be personal to the given patient – not based on statistical outcomes of studies such as the one referenced above.

That’s what the Ovulona™ from bioZhena is for, the tested and the putative uses of which are discussed throughout the bioZhena’s Weblog.

For a pictorial overview with a written narrative, you can go to http://to.ly/VCF (http://s755.photobucket.com/user/vaclavkirsner/library/Second%20album/Pregnancy%20and%20birth%20control%20how-to%20by%20bioZhena?sort=2&page=1 ) and peruse the 6 pictures with brief written explanations of the basics of FIV™, the ovulographic™ monitoring of folliculogenesis in vivo™.

This one of the 6 illustrations, http://to.ly/1k9L, is about “what’s going on here”.  In other words, what is FOLLICULOGENESIS IN VIVO™, the mechanism of the cyclic profiles, the mechanism of menstrual cycles as detected (and passed on to the Ovulona sensor) by the cervix uteri. Should you want to listen to my spoken narrative, click on the image or on the link below.

wealth-of-information-inherent-in-cyclic-profile-signature

The unprecedented wealth of information inherent in the FIV™ cyclic profile

https://biozhena.files.wordpress.com/2016/11/single-slide-narrated-best-wealth-of-info-in-menstrual-cycle-profile-signature.pps

The bottom line is this: The multitude of repeatable features of the cyclic pattern makes it possible to determine the boundaries of the fertile window for every individual menstrual cycle.

A key distinction of our technique is that the “dynamic range” of the cyclic profile data (the vertical span) is the same in all cycles and in all women. This – in addition to the repeatable features of the pattern – facilitates electronic interpretation of the data. Only the timing of the various features varies from cycle to cycle, and we work with that.

The cyclic pattern exhibits a number of well-defined peaks and troughs, with the first post-menstruation minimum (or trough, nadir) occurring typically already on cycle day 6, 7 or 8. That’s the selection stage of folliculogenesis (which follows on the stage of recruitment, days 1 – 5). The signal then rises to a maximum (long-term predictive peak, driven by the maturation of the dominant follicle), the highest reading level of the cycle. Over the next several days, the readings fall toward the minimum before the short-term predictive peak. We have found the ovulation-marker minimum after this short-term predictive peak to correlate with urinary LH and FSH peaks (hormones).

Based on data, we interpret the ovulation marker to be an instantly detected effect of the steroid hormone switch that occurs at ovulation (estrogen to progesterone dominance). The follicular waves, which occur after ovulation [when the non-pregnant system prepares for the next menstrual cycle], cannot remain in place after conception takes place [the regime change is even more profound].

That is the principle of instant detection of pregnancy. Should the conceptus be lost to EEM, Early Embryonic Mortality (miscarriage), the follicular waves come back. That’s the principle of early detection of miscarriage also known as spontaneous abortion [SAB], and of detecting and monitoring the return of the non-pregnant condition.

059q Book of hours

059q Book of hours

Trying to conceive again should be based on the personal FIV™ [FOLLICULOGENESIS IN VIVO™] data generated by the patient, that is, by the woman trying to conceive. This is a principle of evidence-based medicine. Personalized medicine.

STOP PRESS And now, go and check out the 2012 post “The fallacy of ovulation calculators, calendars and circulating-hormone detectors” at https://biozhena.wordpress.com/2012/02/13/the-fallacy-of-ovulation-calculators-calendars-and-circulating-hormone-detectors/

About atrophy, reproductive aging, and how it’s really not nice to fool Mother Nature – or with

June 27, 2010

I have taken it upon myself to popularize Prof. Erik Odeblad’s classic findings about the biophysics of the tissues and secretions of cervix uteri, and how they translate into reproductive physiology and hence to reproductive medicine – at home and in the doctor’s office.

Emeritus Professsor Erik Odeblad

  Emeritus Professor Erik Odeblad    “The cervix is a precision organ as complex as the eye”

My ulterior motive is that I want to be understood when harking back to the British commercial’s exclamation that warned about too arrogant an attitude towards Mother Nature. Or, maybe I aim at the wisdom of the saying (“It’s not nice to fool Mother Nature!”) to be appreciated particularly within the given field of endeavor and/or endeavour – that is, reproductive management. Even if it were only in a segment of it.

In the Alphabet of bioZhena (which is no Alphabet of Ben Sira, though we model on it somewhat), https://biozhena.files.wordpress.com/2007/11/aaee-the-alphabet-of-biozhena.pdf , there is an entry about Atrophy and what it does to a woman as years go by, how “atrophy of mucosal surfaces takes place, accompanied by several problems.”

Jan Amos Komenský (Comenius) Says Farewell to...

Jan Amos Komenský (Comenius) Says Farewell to…

In this blog post I focus on aging – and thus atrophy – of the cervix, leaving aside the inevitable corresponding phenomena in other parts of the reproductive system.

The focus on the cervix is due to bioZhena’s focus on the cervix… which in our scheme of things is the supreme monitor of the complex reproductive goings on that Mother Nature designed in order to cope with all that complexity. After you’ve read the Alphabet article on atrophy, you might scroll down to the entry there about the cervix, which will take you also through cervical cancer and cervical mucus, besides a couple of other things cervical. That will or would be a nice preparation for, or introduction to, what follows.

Prof. Erik Odeblad's sketches from www.woombeuskadi.org...4_erik_odeblad(secrecion_cervix).pdf 13 February 2008

Two sketches by Emeritus Professor Erik Odeblad to illustrate his saying, “The cervix is a precision organ as complex as the eye”. Click (right-click) on the image to see the details. And read on about the details. The fine structure of the cervical canal wall, schematized on the right, is based on examination of mucus samples obtained with a suction syringe from the various parts of the cervical canal of human volunteers for physico-chemical examination.

When, at the inception of the project, we decided to focus on the given part of the anatomy, Erik Odeblad’s work logically and inevitably became a part of the background. He used the NMR (nuclear magnetic resonance) technique of physical chemistry to perform the complicated investigation of cervical mucus, and he produced the classical evidence for the difference between the “fertile” mucus macromolecules that allow the passage of the sperm, and the “infertile” cross-linked glycoprotein molecular network that does not. (To this day I remember his usage of “undulations”…)

In fact, this early information, which involved the thiol-disulfide (sulphydryl-disulphide) redox couples in the glycoprotein macromolecule, had much to do with our early hypothesis of the mechanism of our measurements. Never mind that his work was in the context of the subjective self-examination used in NFP, which did not work for the female member of the team! Had it worked for her, there would probably not be any Ovulona™ for monitoring folliculogenesis in vivo (FIV™ – which has utility well beyond fertility status determination)!

With atrophy being the general biological aspect of aging (and with the initially very large number of ova or eggs in the young female’s ovaries decreasing as she matures and ages), the cervix similarly “undergoes a natural process of development and aging. The surface area of the cervix that is given over to the mucus secreting glands [“crypts”] gradually diminishes with age.”

Odeblad defines three types of the (endo)cervical glands, which he (and others too e.g. Embryology.CH and Eurocytology.EU since at least the 1970s) calls the “crypts”:

  • S crypts produce S mucus, which forms string-like channels and provides transport (“swimming lanes”) for sperm cells. (“Produces a wet, lubricative sensation at the vulva.” That’s for the NFP sympto-thermal method use, the Billings method and/or the Creighton Model NaProEducation Technology method, the classical NFP or FAM – the latter, Fertility Awareness Method, publicized by Ms. Toni Weschler’s 2002 book Taking Charge of Your Fertility .)
  • L crypts produce L mucus, which eliminates low-quality sperm and provides a structure to support what he calls the S and the P mucus. P is a reference to the so-called Peak mucus of NFP or FAM.
  • G crypts produce G mucus, which is “an impenetrable gestagenic mucus formed in the lowest cervical crypts. Prevents sperm entry to the cervix and is part of the immune system which protects the woman’s reproductive system from infection.” A remark from dictionary.com: gestagen (jěs’tə-jən, -jěn’) n. A substance, such as a steroid hormone, that affects the uterus in a manner similar to progesterone. And a remark from a scientific commentator: This G mucus is characterized by the oxidized state of the mentioned redox couples, causing cross-linking in the glycoprotein mucin, which prevents microbes including sperm from entering. Visualize this as closed -S—S- gates (as opposed to the open gate form -SH   HS- of the “reduced” state of the redox couples; “reduced” meaning “electronated and hydrogenated”, the opposite of “oxidized”).
Mondrian_Evolution

Mondrian_Evolution

There are three fundamental principles at work.

1. Natural baseline aging, and this is fundamental – a more or less linear decrease in the number of all three kinds of these glands or crypts, at somewhat different rates: S the fastest, L somewhat slower, G slower still.

2. Slow-down of the aging atrophy by pregnancy.

3. Acceleration of the aging atrophy by the Pill [and/or by other endocrine-active compounds, EACs – this is a logical extrapolation, speculative, but must be assumed].

Now, then.

1. Natural baseline aging, fundamental – a more or less linear decrease in the number of all three kinds of these glands or crypts:

“The number of S crypts decreases from teen age. They are first replaced by L crypts starting at the base of the cervix. Later G crypts replace the L crypts.”

Thus, from Odeblad’s graph [rate reckoned from 15 yrs old to 40 yrs old]:

S crypt baseline decrease or diminution (or atrophy) rate:

50% / 25 years = 2% per year.

At 50 years old, S crypts are at some 10%.

Profile crypts baseline never pregnant never on the Pill

Profile of cervical crypts of a baseline woman – never pregnant & never on the Pill

Representative profile of cervical crypts

(percentage of cervix occupied by active crypts)

for a woman who goes through life without pregnancy or use of the Pill.

This is a baseline profile.

Here is Erik Odeblad’s schematic of the crypts on the surface of the cervical canal:

Cervix of a 20 year old virgin

Carefully mapped lateral wall of the cervix of a 20 year old virgin           (reported by Emeritus Professor Erik Odeblad, Department of Medical Biophysics, University of Umeå, S-90187, Umeå, Sweden)

This is Professor Odeblad’s artist’s impression of cervical mucus secretions:

Mucus secretions

Schematics of cervical mucus secretions

Key to colors:

Blue         = S mucus

Yellow     = L mucus

Red          = G mucus

Green      = P mucus of which there are several sub-types

Pink         = Z granules

Professor Odeblad’s explanatory notes:

Z granules – the enzyme in the Z granules combines with the P mucus to create a liquefying effect.

P mucus – there are a number of sub-types of this mucus, the most relevant for fertility are P2 and P6. P2 could be present as early as the beginning of the fertile phase possibly having a role in liquefying the G mucus. P6 is mostly confined to the upper part of the cervix, occurring close to the Peak of fertility, and having a role in conveying sperm. It creates a very wet and lubricative sensation at the vulva.

F mucus – comes from the cells scattered throughout the length of the cervical canal and has no known special function.

For a recent evidence of four different morphological mucus types, namely L, S, P and G, see “Morphological characterization of different human cervical mucus types using light and scanning electron microscopy” by M. Menárguez, L.M. Pastor and E. Odeblad, Human Reproduction, Vol. 18, No. 9, 1782-1789, September 2003 –  http://humrep.oxfordjournals.org/cgi/content/full/18/9/1782

Citation: “The distribution of crypt zones in the cervix depends on age, number of pregnancies and use of contraception. In a non-pregnant woman, aged 25–30years and not having used contraception, the cervix averages 22 mm in length and 6 mm in diameter at ovulation. The crypt distribution starting from below and moving upwards is as follows: the G crypts dominate in the lowest 4–5 mm; then there is a zone of L crypts occupying the next 9–10 mm; this is followed by the S zone, for 5–6 mm; and the highest 3–4 mm contains the P crypts.”

When you read the paper, you detect that he has a very special knack for sampling the respective mucus types from the said crypts. Hat off! Work with human experimental subjects is no stroll in the park, to put this mildly.

2. Slow-down of atrophy aging by pregnancy:

Profile crypts 4x pregnant

Profile of cervical crypts of a 4x pregnant woman

Representative profile of cervical crypts

(percentage of cervix occupied by active crypts)

for a woman who goes through life with four pregnancies and no use of the Pill.

Pregnancy – S crypt diminution rate from Odeblad’s graph

[4 pregnancies, no Pill, rate reckoned from 15 yrs old to 40 yrs old]:

30% / 25 years = 1.2% per year.

At 50 years old, S crypts are at some 20%.

3. Acceleration of atrophy aging by the Pill [and/or by other endocrine-active compounds, EACs – a logical extrapolation]

Profile of cervical crypts of a woman on the Pill

Representative profile of cervical crypts

(percentage of cervix occupied by active crypts)

for a woman who goes through life without pregnancy and uses the Pill for 10 years

Pill – S crypt diminution rate from Odeblad’s graph

[no pregnancy, Pill for 10 years (18 to 28 yrs old), rate reckoned from 15 yrs old to 40 yrs old]:

60% / 25 years = 2.4% per year.

At 50 years old, S crypts are at some 5%.

This includes the slow down of the diminution gradient during the last 12 years of no Pill.

Compare this with diminution/atrophy rate during the 10 years on the Pill:

65% – 25% = 40% / 10 years = 4% per year.

This is double the baseline rate of cervical atrophy.

It’s more than 3 times higher than the pregnancy-slowed atrophy rate.

Three concluding remarks by Prof. Odeblad:

“Regression when taking the Pill is different for estrogen-dependent crypts (L and S) and progesterone-dependent crypts (G) which may in part overdevelop.”

“The study of the effects of contraceptive pills on the cervix is a difficult task. A considerable amount of work is required for each patient and the time required spans many years, up to 10 years or more. Many women also want to change to other pills or to other methods of contraception, or perhaps now want to become pregnant. It also happens that some pills are withdrawn from the market. To these difficulties are added the normal age changes in the cervix and the dynamic processes which are of constant occurrence. 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.” (“Some Notes on the Cervical Crypts”, Dr E. Odeblad, Bulletin of the Ovulation Method Research and Reference Centre of Australia, Vol 24 No 2 June 1997, p31)

Citations and graphics reproduced from http://www.billings-ovulation-method.org.au/act/cervix/ageing.shtml .

“Complications arising from the use of the Pill are very frequent. Infertility after its use for 7-15 years is a very serious problem. S crypts are very sensitive to normal and cyclical stimulation by natural oestrogens, and the Pill causes atrophy of these crypts. Fertility is impaired since the movement of sperm cells up the canal is reduced. Treatment is difficult.” He also wrote: “After 3 to 15 months of contraceptive pill use, there is a greater loss of the S crypt cells than can be replaced … A pregnancy rejuvenates the cervix by 2-3 years, but for each year the Pill is taken, the cervix ages by an extra year.” Web reference:  http://www.billings-ovulation-method.org.au/act/pill.html .

Comment on implications for treatments of certain symptoms

For example, the suggested method [Weschler, Toni (2002). Taking Charge of Your Fertility (Revised ed.). New York: HarperCollins. p. 52] of thinning cervical mucus to help achieve pregnancy by taking the OTC expectorant drug guaifenesin, which is thought to act by increasing the volume and reducing the viscosity of secretions.

The drug is also used to treat the symptoms of primary dysmenorrhea [severe uterine pain during menstruation ] where another treatment of choice is combined oral contraceptives [COCs]. Such treatments are administered to adolescents as well as to mature women because dysmenorrhea is a very common and serious problem (25% of women and up to 90% of adolescents ).

In both cases, the expectorant and the contraceptives are administered without knowledge of their mechanism of action in the given problem. Focus is on treating symptoms, not the underlying causes. The patient is the detector of any effect. How does the expectorant drug use correlate with the secretions of the different types of cervical mucus on the one hand, and with the folliculogenesis cyclic profile on the other? Is there any connection? If not, what does the drug do to the different crypts? And what the COCs do to them?

Is the expectorant so selective that it might do the right thing? Reduce type G? Enhance type S mucus? Does oxidation of the guaifenesin help reduce the cross-linked mucin type G in the cervical canal? As simple and pretty as that? (Even prettier if guaifenesin were not to be an EAC, an endocrine-active compound … which inactivity does not look likely – http://www.who.int/ipcs/publications/en/ch3.pdf .)

Would it not be nice to have a rationale for how the small guaifenesin molecule can have a good effect on both sub-fertility/infertility and dysmenorrhea?

Could it be that guaifenesin works bioelectrochemically in the same oxidation-reduction (redox) manner on the enzyme cyclooxygenase in the prostaglandin cascade, which is a cascade of redox reactions – producing an anti-inflammatory effect that translates as suppression of pain? (On a personal note, why not capitalize here at least conceptually on our ancient Wellcome Research Labs work, even before receiving – presumably – the first pension money from Glaxo Smith Kline?)

It’s easier to contemplate in general the effect of the contraceptive drug, which will presumably depend on the contents of the estrogenic and gestagenic components (modeling on Odeblad’s findings)…

Is there a connection between pain, cervix and ovaries, ovarian reserves? Maybe an abnormal depletion of, via ovarian cysts? Will the number of follicular waves and/or other features in the Ovulona cyclic profile – and correlated with ultrasound and MRI – show any such abnormality? Might the Ovulona be useful for diagnosis here, convenient, simple (inexpensive)? Wouldn’t that be nice?

Is cyclooxygenase inhibition detected by the cervix, does it show in the cyclic profile? Does said prostaglandin synthesis inhibition alter the number of follicular waves – while reducing the pain?

Answers to questions like these are needed. Keep in mind that ovulation is an inflammatory process, and since we detect it in the cyclic profile, it is reasonable to pose the above prostaglandin theory questions about the COX-2 (cyclooxygenase) inhibition.

Summarizing Odeblad’s results and the take-home message:

Baseline outcome of cervical S crypts aging: S crypts down to 20% at 40 years of age. Here you have the reason why mature age leads to sub-fertility and to infertility.

Atrophy slow-down effect of 4 pregnancies: S crypts down to 40% at 40 years of age. Here you see Mother Nature’s design in action. Pregnancy slows down the inherent rate of cervical aging (atrophy, deterioration). Naturally, this is not to argue for 4 pregnancies per lifetime – it’s merely how the effect was made measurable.

Atrophy acceleration effect of 10 years on the Pill: S crypts down to 10% at 40 years of age. Here is why it’s not nice to fool Mother Nature, why it’s not good to mess with her design. The Pill is an archetypal anthropogenic Endocrine-Active Compound [man-made EAC], and it was brought up in the previous post how there are very many of these EACs, all insulting the female body and health, some – like chemical contraceptives – by design.

While the story of Laodamia and Protesilao is touching, I merely want to ask that girls, ladies and their physicians do not moon the messenger.

Laodamia

STOP PRESS

And now, go and check out the 2012 post “The fallacy of ovulation calculators, calendars and circulating-hormone detectors” at https://biozhena.wordpress.com/2012/02/13/the-fallacy-of-ovulation-calculators-calendars-and-circulating-hormone-detectors/


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