Folliculogenesis In Vivo(TM)

Brief sketch of the basic reproductive endocrinology

Ovarian follicles are tiny fluid-filled sacs containing immature egg cells that are periodically initiated to grow and develop, culminating in ovulation. This is how it goes:

The peptide called follicle-stimulating hormone (FSH), which is released by the pituitary gland of the brain, primarily functions to induce proliferation of the follicular granulosa cells in one of the two ovaries and to stimulate an aromatase enzyme for estrogen synthesis.

The other pituitary peptide, luteinizing hormone (LH), then stimulates the transformation of estrogen-secreting stromal cells in the selected ovary into progesterone-secreting cells, and promotes ovulation. (The LH alone is tested for in the urine by the so-called OPKs, Ovulation Prediction Kits.)

The predominant ovarian hormones, which exert peripheral, central and intra-ovarian effects, are the sex steroids estrogen or estradiol (E2) and progesterone (P4). There are also other steroids at play in the ovarian and hypothalamic-pituitary events, and there are also other peptidic reproductive hormones known as non-steroidal ovarian factors (e.g., inhibin, oocyte maturation inhibitor, gonadotropin surge-inhibiting factor, and certain growth factors).

Key take-home message:

Proper brain-ovary orchestration is the absolute requirement

The properly orchestrated actions of all the variously secreted substances are known to be necessary for the functioning of the menstrual cycle.

The endometrium is the glandular mucous membrane lining the uterus (or womb),  and the cervix uteri is the glandular “neck of the womb”; they are very sensitive detectors of the hormonal signals and of their orchestration, that is of the relative timing of the brain-ovary hormonal signals with respect to each other.

Said proper orchestration is the absolute prerequisite of properly working female reproductive mechanism, i.e., folliculogenesis. The Ovulona sensor monitors folliculogenesis.

Explanation of Folliculogenesis With Pictorial Summary

High-level definition

The periodically recurring development of ovarian follicles, in preparation for the periodically recurring ovulation, is called folliculogenesis. The process of folliculogenesis is the essence of ovarian function, and its dynamics is an absolute need-to-know for fertility status determination.

Folliculogenesis involves four basic conditions in which the many follicles – present from birth in the two ovaries – can be found. The four conditions are: resting, growing, atretic, or ready to ovulate [A.L. Goodman and G.D. Hodgen, in R.O. Greep, editor: Recent progress in hormone research, Academic Press, 1983].  Most of the follicles remain resting but, periodically in every menstrual cycle, a group of follicles are “recruited” to grow. Only one of these will mature and will normally ovulate, with the rest of the group succumbing to atresia (death).

It is well established that women and other primate females produce a single fertilizable egg approximately every four weeks, but that the actual duration of this circamensual (or approximately one-month) period is not a constant. Rather, the period ranges from about three weeks to about five weeks.

Therein lies the need for and the challenge of reliable monitoring of the menstrual cycle, and of reliable anticipation of the brief fertile window (less than 5 days; arguably – until we prove it definitively in large clinical trials – only 3 days).

Very short fertile phase (aka fertile window)

detected via the cervix uteri

The short duration of the fertile phase is due to the very limited life-time or viability of the ovulated egg (i.e., the egg released from the successfully matured dominant follicle) coupled with the pre-ovulation fertile days that are due to the functional life-time of the sperm. The egg is thought to be fertilizable for only about 8 to 12 hours after ovulation (though some estimates have been for up to 24 hours after ovulation).

According to Speroff, Glass and Kase’s authoritative monograph on gynecologic endocrinology, “equally uncertain is knowledge of the fertilizable lifespan of human sperm. The most common estimate is 48 – 72 hours”, which means that the sperm is thought to be capable of fertilizing the egg for up to at most 3 days after being deposited in the vagina.

The sperm survive longer than the ovulated egg but only in the temporarily hospitable environment of the cervical mucus and epithelium turned hospitable just briefly before ovulation. Outside of that narrow window, the mucus is inhospitable to sperm, and prevents their and other microbes’ entry into the uterus. Allowing for the longer longevity of the sperm is the most difficult challenge for scientific family planning.

We have the definitive solution because we track the end-organ effects of all the inputs into the system. This affords reliable quantitative anticipation AND DETECTION of the ovulation event, both of which are necessary data (because of said dependence of sperm viability on the close proximity of ovulation).

The definitive solution is achieved by the unprecedented tracking of the dominant follicle maturation that varies from cycle to cycle, and that is followed by the unique short-term predictive peak, which drops into the ovulation marker nadir in the menstrual cyclic profile (aka the 5th vital sign signature).

Details of folliculogenesis concluded with visual summary of

Folliculogenesis-In-VivoTM

Folliculogenesis is a continuous process with well-defined morphologic and endocrine dynamics or timing of events. The dynamics of this process have been characterized biologically, and separated into the four intervals or stages of recruitment, selection, dominance and ovulation [G.D.Hodgen, Fertility and Sterility 38:28 1, 1983]. While in real life the timing of the last two stages is highly variable (see, e.g., the three cycles in the illustration below), in terms of the stereotypical menstrual cycle, the timing of the stages of folliculogenesis is as follows:

Timing of the 4 stages of folliculogenesis

The interval of recruitment begins at the end of the previous cycle, from the onset of menstrual bleeding to approximately day 5 to day 7 of the current cycle. During this interval, LH from the brain induces a factor from the ovarian theca cells that increases the blood supply and estrogen synthesis by the recruited follicles.

The term selection indicates the reduction of the recruited group of follicles down to the species-characteristic ovulatory quota, which in women and related primates is one. Selection is the culmination of recruitment on day 6 ± 1. Typically only one of the two ovaries sponsors recruitment and selection of the single dominant follicle, which is destined for ovulation.

Dominance is the interval of follicular growth that precedes ovulation after selection, and is achieved “typically” between days 8 and 12 of the stereotypical menstrual cycle. It appears that it is the one follicle most rapidly acquiring aromatase activity and LH receptors that becomes dominant, thus overcoming an ovarian inhibitory activity that suppresses the less-developed follicles of the recruited group.

This happens in the mid-follicular phase [the phase before ovulation]. Increasing quantities of estrogen are secreted by the dominant follicle and play a critical role in coordinating the development of the different parts of the reproductive tract: Estrogen priming is essential in the brain as well as in the cervical epithelium and mucus, and in the oviduct.

The sensor readings rise with the rising estrogen and fall with increasing progesterone as has been found in separate experiments in three mammalian species (bovine, porcine and [menopausal] human).

The dominant follicle has a straightforward prerogative: It must synchronize the entire reproductive system for ovulation, fertilization and implantation. Failing that synchronization task, conception will not be possible (such as in the case of the luteal phase defect, a frequent cause of failure to conceive).

Ovulation: Once the dominant follicle has achieved the necessary size and adequate hormonal effects, final maturational changes within the follicle stimulate ovulation. Endocrinologically, the most prominent marker of impending ovulation is the LH surge, which anticipates ovulation within 9 to 12 hours, and which is under the control of the ovarian pacemaker that dictates the timing of these events.

At the time of the LH surge, the granulosa cells surrounding the follicle become transformed or “luteinized”. They become specialized toward synthesis and secretion of progesterone and this rapid increase in progesterone levels is responsible for inducing and coordinating several physiological changes in the reproductive system. The ovulation marker dip or minimum in the Ovulona cyclic profile detects one of the changes, due to the sensitivity of the epithelium and mucus in the posterior fornix region to the sex steroids.

Here is a condensed pictorial summary in terms of how we track the process. It is best viewed in the slide form – the image is a screenshot of the last of the 3 slides accessible at https://biozhena.files.wordpress.com/2018/03/wealth-of-info-elucidation-silent-3-slides-animated-ed.pps

Wealth of info and elucidation of dominant follicle peak

R… Recruitment on days 1 to 5 ± 1 (data captured usually only after blood flow – due to hygiene concerns). S… Selection on day 6 ± 1. GC+TC E2up… Dominant Follicle Maturation: Granulosa and Theca Cells produced Estradiol (E2) rises, which drives the signal up; Dominant Follicle also initiates expression of LH Receptors. GC P4up… After the appearance of LH Receptors, the preovulatory Granulosa Cells secrete Progesterone (P4), which drives the signal down. (That’s also why the ovulation marker is a trough, the lowest minimum in the menstrual cyclic profile.) Ref.: Page 39 of 23rd Edition of Williams OBSTETRICS © 2010, 2005, 2001 by The McGraw-Hill Companies, Inc. (www.gums.ac.ir/Upload/Modules/Contents/asset39/williams23.pdf)

The Ovulona™ Determining the Fertile Window

The most important feature to point out about the Ovulona-generated cyclic pattern is that, while certain amplitude thresholds are constants set by the calibration of the sensor electronics, the boundary days of the fertile window (the beginning and the end of fertility, respectively) are variables that change from cycle to cycle as well as from woman to woman.

This is the fundamental advantage and superiority over any prior art technique: While the dynamic range (vertical span of measurement data) is woman- and cycle-independent, the opposite holds for the timing, which the biology causes to vary from cycle to cycle – and we monitor it and work with it.

Ovulona & Ovulograph w. links - Friendly Tech

Review three slides on how we monitor folliculogenesis in vivo with the Ovulona, which will, in due course, be transformed into a telemetric cervical ring:

https://biozhena.files.wordpress.com/2018/04/folliculogenesis-in-vivo-the-ovulona-and-the-cervical-ring.pps

The image is a screenshot of the third slide, which is animated and has clickable links to further information.

 

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