Getting Pregnant Naturally, Part 2

How to Get Pregnant
by Sherman J. Silber, M.D., F.A.C.S.

(Page 2 of 2)

How a Primitive Region of the Brain Called the Hypothalamus Controls the Menstrual Cycle

The entire cycle of follicle development, ovulation, and menstruation depends upon the precisely timed release of FSH and LH from the pituitary gland. In the male, FSH and LH production is constant, and therefore, sperm and hormone production are constant. In the female, there is a delicately synchronized increase in FSH at the beginning of the cycle to promote follicle growth, an LH surge at midcycle to promote ovulation, and then a gradual drop in pituitary hormones that causes a drop in estrogen and progesterone production by the ovary, resulting in menstruation.

We know that the release of FSH and LH from the pituitary is controlled by a hormone called GnRH (gonadotropin-releasing hormone), which originates in a primitive region of the brain called the hypothalamus.

The hypothalamus sits right at the base of the brain and above the pituitary gland, and causes the pituitary to release FSH and LH by sending the hormone GnRH directly to it. It used to be thought that the brains of males and females were different in this regard (and indeed they are in most other animals).We now know that this area of the brain in humans functions identically in the male and female, and that it is the ovary that directs the cyclical production of FSH and LH in the female pituitary.

By releasing GnRH, the hypothalamus is simply permissive in allowing the pituitary to stimulate the ovary in the female and the testicle in the male. The brain secretes small pulses (lasting only a minute or so) of the hormone GnRH about every ninety minutes in both men and women. It is the periodic, never-ending release of GnRH from the brain that causes the pituitary gland to start secreting FSH and LH, bringing on puberty, including menstruation in girls.

In men with deficient sperm or testosterone production, the FSH and LH levels are higher because the pituitary is overworking in an effort to compensate. The same phenomenon occurs in women. We know that when the ovary runs out of eggs, and women can no longer produce estrogen (thereby going into menopause), the FSH and LH levels from the woman's pituitary go sky-high in an effort to stimulate what little ovarian reserve may still exist.

To understand estrogen's role in controlling the pituitary hormones, we must look at what happens at midcycle in the woman. The surge in estrogen at midcycle causes the pituitary to suddenly release a high amount of LH (along with some extra FSH), and this stimulates ovulation. The cyclic pattern of hormone production in the female, which is quite different from the constant pattern of hormone production in the male, is not caused by any difference in the female brain's release of GnRH. If the hypothalamus of any human being were destroyed (male or female), there would be no further GnRH secretion, the pituitary would cease to make FSH and LH, and the ovaries or testicles would shrivel up and completely stop functioning.

Clinical Importance of GnRH Release from the Brain for IVF

Why is the fascinating relationship of a primitive region of the brain to the pituitary, the ovaries, and the testicles so important? It bears very heavily on how we can obtain the best-quality eggs from the female for IVF.When the ovaries are stimulated to make more eggs by administering FSH (a necessary step in the in vitro fertilization process), the tremendous increase in estrogen production over a normal level can cause an early increase in LH secretion. This may result in premature ovulation with complete loss of the eggs or, at best, may hurt the subsequent pregnancy rate resulting from those eggs. In order to prevent this premature LH increase, we need to have a better understanding of GnRH, the hormone from the brain that allows the pituitary to release FSH and LH.

If GnRH were released constantly rather than at pulsatile intervals of ninety minutes, a peculiar reverse phenomenon would take place. The pituitary, rather than being stimulated to release FSH and LH, would become completely paralyzed after two to five days and would no longer secrete any FSH or LH until the constant release of GnRH was stopped and regular pulsatile ninety-minute secretion was resumed. Thus, we can completely turn off the pituitary whenever we want to by simply giving a constant rather than intermittent dose of GnRH. It's as though the pituitary needs a ninety-minute rest before each new GnRH stimulus in order to function properly. If the pituitary doesn't get this ninetyminute rest, it behaves just as though there were no GnRH at all. This process is called down regulation.

GnRH is chemically a very simple hormone called a polypeptide, which can be easily synthesized by drug companies.When a small modification is made in the structure of the GnRH, we have what is known as a GnRH agonist,which, if injected just one time a day, stays around in the bloodstream at a constant level rather than being immediately destroyed within minutes, as the brain's normal GnRH would be. Thus, giving an injection of GnRH agonist once a day creates the same effect as infusing a constant level of GnRH all day long and giving the pituitary no rest.When you give the pituitary no rest, at first it pours out a lot of FSH and LH, but then several days later, the depleted pituitary can no longer release LH or FSH.

There are several GnRH agonists on the market, Lupron (leuprolide) being popular in the United States, and Suprefact (buserelin) being a popular one in Europe. Using Lupron along with a stimulation cycle completely turns off the pituitary and prevents a premature LH surge that would interfere with the proper development of the large number of eggs necessary for IVF.

A different variation of GnRH analogue is the GnRH antagonist, e.g., Cetrotide or Antagon. Instead of depleting the pituitary of FSH and LH, as Lupron does, GnRH antagonists work by directly and immediately blocking the pituitary's release of FSH and LH by preventing GnRH from having any stimulating effect on the pituitary.

How Do Hormones Genetically Prepare the Egg for Fertilization?

Incredible genetic cellular changes take place in a woman's developing eggs each month, beginning with the elevation of FSH at the start of menstruation. Very complex events are taking place in the egg during this monthly development and growth of the follicle. Furthermore, the release of LH stimulated by the estrogen surge at midcycle does much more than just cause ovulation. It finalizes the critical genetic preparation of the egg, without which fertilization would be impossible.

Thus far, only a superficial description of what happens during a menstrual cycle has been given: (1) follicular growth and estrogen production in the first half, (2) ovulation at midcycle, hopefully with fertilization, and (3) preparation of the uterine lining for embryo implantation in the second half of the cycle, stimulated by the production of progesterone from the corpus luteum (newly formed from the ovulated follicle). But these events are only the outward signs of an intricate genetic preparation for fertilization.

Reduction Division (Meiosis) of the Egg's Chromosomes

Every cell in the body has forty-six chromosomes consisting of twenty-three pairs, which carry all of our genes. However, the sperm and the egg at the moment of fertilization must each have only twentythree single chromosomes, not forty-six, so that when the sperm and the egg unite, the fertilized egg has the normal number of chromosomes.

Like every other cell in the body, sperm precursors in the testicle have forty-six chromosomes. But in the process of sperm production, the chromosomes are reduced to half the normal number by a process called meiosis. So when sperm leave the testicle, they have only twentythree chromosomes. The eggs also have forty-six chromosomes until the very moment the sperm penetrates an egg and initiates fertilization. Fertilization cannot possibly occur unless the egg's forty-six chromosomes can be reduced to twenty-three. The moment the sperm penetrates the egg, half of the egg's chromosomes must be extruded. Then two half sets of chromosomes, one from the male, and one from the female, merge into a new individual with the normal number of fortysix chromosomes. Without the hormonal stimulation of FSH causing follicle development, followed by the release of LH at midcycle, the eggs would not be genetically prepared for this complex event of meiosis to occur.

The miracle of this separation of chromosomes is the most complicated event in the whole reproductive process; it determines the genetic makeup of the child and results in the genetic variability of the offspring.

Development of the Egg During Growth of the Follicle

At the time of a woman's birth, all of her eggs are fixed in the beginning phase of the first meiotic division. The remaining stages of the meiotic division will not begin until years later, when her egg has finally matured in a developing follicle and the LH surge at midcycle causes the egg to resume meiosis. This resumption of meiosis, triggered by LH, would not occur without the prior preparation by FSH (meiotic competence) during the first two weeks of the cycle.

At the beginning of the cycle, from day one of menstruation, increased FSH production from the pituitary stimulates rapid growth in the egg. The egg will grow during this early follicular phase from a tiny 30 microns to its normal mature size of 140 microns (from 1/1,000 of an inch to approximately 1/200 of an inch in diameter). At this time, the very tough outer membrane, the zona pellucida, forms around the enlarging egg. Next, the follicle expands to form a fluid-filled cavity around the egg. The tiny forming follicle is visible on ultrasound at this point.

When the follicle forms, many compact layers of granulosa cells begin to surround the now enlarged egg, and the outer sheath of these granulosa cells produces the hormone estrogen. Even a brief deprivation of estrogen to the maturing egg during this stage will result in the egg's immediate death. If FSH stimulation were to suddenly cease or be reduced dramatically, estrogen production by the granulosa cells would decline and the egg would die.

The egg remains embedded on one side of the follicle in a mound called the cumulus oophorus. The cells around the egg remain compact until the egg is ready for fertilization.When LH triggers the important genetic events that will allow fertilization after ovulation, these cells spread out in a radial pattern, giving a sunburstlike appearance referred to as corona radiata. If this widely dispersed appearance of cumulus cells surrounding the zona pellucida of the egg is present, physicians performing in vitro fertilization know that the egg is adequately mature for fertilization to occur. It is the most easily observable sign that the egg has gone through enough FSH stimulation to be ready for the genetic events of meiosis, which will ultimately lead to the possibility of fertilization.

It is quite astounding that there is little difference in the maximum diameter of the egg of almost any species, even though the size of the follicle containing the egg is generally related to the size of the animal. Thus, eggs of a whale could easily pass through the oviduct of the smallest mammal, like a rat, even though the whale's follicle containing that small egg could easily be as large as a whole rabbit. The increasing size of the follicle has nothing to do with any increase in the size of the egg but is merely an indication that the egg is being properly prepared for what it has to do when it receives the surge of LH at midcycle.

Resumption of Meiosis After the LH Surge

LH begins the resumption of meiosis, but the penetration of the egg by a sperm is what causes the completion of that process. After the LH surge, the first meiotic division occurs, but this division does not reduce the number of chromosomes. This is an equal division in which fortysix chromosomes are still left within the egg nucleus. Actually, it is more complex than this, and I will explain it in detail in chapter 12. The "first polar body" is a small, divided nucleus that is pinched off from the main body of the egg prior to ovulation, about thirty hours after the LH surge. The extrusion of the first polar body from the egg shows that the first meiotic division has occurred under the influence of LH, meaning that the egg is now prepared to undergo the all-important second meiotic division. Many college biology students get confused by these two stages of meiosis. In the first division, all the chromosomes partly divide but do not split completely. In the second division, they actually complete the split. The egg is thus prepared during meiosis for the entrance of a sperm.

Penetration of the Egg by a Sperm

For a sperm to enter and fertilize the egg, it must dig its way through several layers of protective shields surrounding the egg. These outer walls safeguarding the inner confines of the egg represent an impressive barrier to sperm penetration, and a sperm cannot dig its way through these membranes without the aid of chemicals released from its warhead, the acrosome. The acrosome surrounds the front portion of the sperm and acts much like a battering ram. Chemicals released by the acrosome first dissolve the jellylike cumulus oophorus, enabling the sperm to pass through it and reach the tough zona pellucida. This very tough membrane, like the shell of a chicken egg, represents perhaps the most formidable obstacle to sperm. To penetrate this barrier, the sperm cannot just haphazardly liberate chemicals, or the egg might be damaged. The attacking chemicals must remain closely bound to the surface of the sperm and thereby cut an extraordinarily narrow slit into the membrane.

In order for the sperm to make its way through the sturdy zona pellucida, a process called the acrosome reaction is necessary. The acrosome is attached around the front two-thirds of the sperm head, where it is positioned much like an arrowhead. Its contents are tightly contained because premature leakage of acrosin (the dissolving chemical) would make it impossible for the sperm head to drill its way through the zona pellucida when it finally makes contact. Contact with the zona pellucida stimulates the acrosome to undergo its reaction, during which holes form in the inner and outer acrosomal membranes and acrosin is released, helping the sperm break through the zona pellucida.

Once a lucky sperm makes contact with the zona pellucida (which is purely a random event), it takes a minimum of fifteen minutes before penetration can begin. Some sperm can be seen struggling for as long as an hour before they make their initial penetration. If penetration hasn't occurred within an hour, however, something is wrong and the egg probably won't be fertilized. Sperm enter the zona pellucida at an angle almost exactly perpendicular to the surface of the egg and appear to develop a channel within the zona as they move forward. Despite the important "drilling" effect achieved by the release of acrosin from the outer acrosomal membrane of the sperm head, it is very clear that without the vigorous, hyperactive beating of the sperm tail providing strong mechanical propulsive force, the sperm still would not be able to get in.

Once penetration of the zona has begun, it requires an average of twenty minutes for the sperm to get completely through; once the sperm has broken through, it plunges directly into the egg membrane itself in less than a second. At that moment, the sperm tail immediately becomes paralyzed. Otherwise the thrashing of the sperm within the egg itself would kill the egg. Very soon after the sperm head becomes embedded in the egg, its tightly packed DNA begins to decondense (spread out a little), and the genetic material of the male becomes the male pronucleus.

Completion of Meiosis and Union of the Male and Female Genes

Once the first sperm has successfully invaded the zona pellucida of the egg, a remarkable event takes place. The membrane that surrounds the egg within the zona fuses with the membrane of the sperm, and the sperm and the egg become one. The egg literally swallows the sperm as these two microscopic entities initiate the development of a new human being. Also at this moment the outer zona pellucida becomes transformed into a rigid barrier so impenetrable that other sperm, despite all the chemicals in their acrosomes, cannot possibly enter. Many sperm can be seen attempting to enter the egg in competition with the one that made it first, but their efforts are in vain. Once the egg has been successfully penetrated by a single sperm it shuts its walls so tightly that none of the followers can get through. This protects the fertilized egg from the entrance of extra chromosomes (called polyploidy), which would cause a genetically impossible fetus, and a miscarriage.

Penetration of the egg membrane by the sperm head also sets in motion the second meiotic division of the egg with the release of the second polar body. It is this second meiotic division that reduces the number of the egg's chromosomes to half so that sperm and egg genes can unite. When the sperm head enters the egg, its chromosomes are tightly and densely packed. After fertilization, the sperm head, with its twenty-three chromosomes, expands (decondenses) into what is called the male pronucleus. At the same time, the female nucleus (which is sitting on the opposite side of the egg) is triggered to undergo its second meiotic division shortly after sperm penetration and become the female pronucleus. This second meiotic division causes extrusion of half the egg's chromosomes to the second polar body, leaving the female pronucleus with twenty-three, just like the sperm. Within eleven to eighteen hours the male and female pronuclei sitting on opposite sides of the egg appear extremely prominent and get ready to converge.

This is truly an amazing event. The two pronuclei (each with twentythree chromosomes) slowly and majestically move toward the center of the egg and join into one nucleus, which now has forty-six chromosomes and represents an entirely new human being. This merging of the male and female pronuclei is called syngamy. After syngamy, the fertilized egg is ready to divide. Division of the fertilized egg is called cleavage.

Early Development of the Fertilized Egg

Over the next three days the fertilized egg first divides (cleaves) into two, then four, then eight cells. The first cleavage into two cells occurs sometime before thirty-eight hours after penetration by the sperm. The second cleavage (four cells) begins sometime between thirty-eight and forty-six hours after fertilization. The third cleavage (eight cells) begins between fifty-one and sixty-two hours after fertilization. If any one of those cells were to be removed, the remaining ones would still continue to develop into a normal baby. That is, each cell is still totipotent, and the remaining cells could develop into a completely normal human being. Each one of these early cells formed by the first three or four divisions of the fertilized egg is called a blastomere.

Finally, by the fourth day, the embryo has 64 to 160 cells and is called a morula. These cells have now "compacted" and are no longer totipotent. It's at this stage that the embryo is passed from the fallopian tube into the uterus. By the fifth or sixth day after fertilization, there are so many cells still packed into the same hard, tough zona pellucida that individual cells can no longer be recognized. At this stage the embryo is called a blastocyst. On the sixth or seventh day after fertilization this blastocyst thins out a spot in the otherwise hardened shell of the zona pellucida and actually "hatches," just like a chicken hatches from its shell in an incubator. The blastocyst pushes its way out of this thinned-out crack in the zona pellucida and prepares for implantation (by the seventh day) into the wall of the uterus, or womb. Up until now the zona has protected the embryo. But as a blastocyst, the embryo is now ready for its most treacherous moment when it has to attach to the endometrial lining of the womb.When the blastocyst attaches successfully to the endometrium, that initiates pregnancy.

Pregnancy Testing

If a pregnancy has been achieved, seven days after fertilization, the embryo begins to secrete the hormone HCG (human chorionic gonadotropin), and this HCG stimulates the ovary to continue to produce progesterone and estrogen, which are necessary for the maintenance of the lining of the womb. Without continued production of progesterone, the pregnancy could not survive. The embryo begins to make HCG when the pregnancy is first established in the uterus, about seven days after ovulation. After three months the fetus, or rather the fetal placenta, actually makes its own progesterone, and the ovaries are no longer needed for production of hormones. After nine months, the baby is ready to be pushed out of the uterus by the mother during labor.

The presence of HCG only signifies that the embryo has implanted and is the basis for almost all of the routine pregnancy tests. Blood tests for pregnancy really just check for the presence of HCG. If it is present, then the pregnancy test is positive. Pregnancy can even be diagnosed with a simple urine test that the woman can perform herself within fourteen days of egg fertilization. However, the laboratory blood test is more reliable. If it is positive, i.e., there is more than twenty-five units of HCG, it should be repeated two days later to see if the HCG level has increased. Normally the HCG doubles every two days for the first month of pregnancy and reaches astronomic levels. If the HCG does not increase, a miscarriage is very likely, and the pregnancy is referred to as a chemical pregnancy.

If the HCG level goes up as it should, then an ultrasound five weeks after fertilization (defined as a seven-week gestational-age pregnancy) should show a normal fetal heartbeat. If there is no fetal heartbeat by seven weeks' gestation, the pregnancy is not viable and miscarriage will follow. Thus, a positive pregnancy test alone does not ensure that the pregnancy is viable. For that you must have an ultrasound exam.

When you have a positive pregnancy test (which just means an elevated HCG level), the chances are 85 percent that you will have a favorable ultrasound at seven weeks and deliver a healthy baby. But miscarriage occurs commonly in early pregnancy despite an elevated HCG level. Because of the biological clock, miscarriage is more common in older women than in younger women.

Copyright © 2005 by Dr. Sherman Silber

About the Author

Sherman J. Silber, M.D., F.A.C.S., is an internationally known pioneer in infertility treatment, and is medical director of the Infertility Center of St. Louis at St. Luke's Hospital in St. Louis, Missouri. Infertile couples come from all areas of the world for treatment at his center. Dr. Silber invented the microsurgical vasectomy reversal, testicle and ovarian transplantation, and he developed the sperm aspiration and ICSI techniques for previously hopeless cases of male sterility. He is the author of four medical textbooks, more than 180 scientific papers on human fertility and reproduction, and the bestseller How to Get Pregnant, and How to Get Pregnant with the New Technology. A popular guest speaker, he has appeared numerous times on Donahue, Oprah, Joan Rivers, The Today Show, and Good Morning America.