This page reviews basic biology helpful in understanding modern physiology and how Chinese medicine can improve your health and fertility. This is particularly important information for women with poor ovarian reserve (high FSH).
GENETICS AND EPIGENETICS
Chromosomes are packages of genetic material consisting of a DNA molecule, which contains many genes, and that DNA molecule has many proteins attached which maintain chromosome structure and play a role in genetic expression. A single gene is a unit of DNA within a chromosome that can be activated to transcribe a specific RNA. Another definition of gene is a section of DNA that contains the code for specific proteins that build functional molecules essential to human life. The double-stranded helical structure of DNA is replicated...it is estimated that the original DNA molecule present in the fertilized zygote (fusion of sperm and egg) must be copied 10^15 times during the course of a human lifetime! Errors are surprisingly rare!
Our DNA is contained within the cell nucleus, and also within the cell mitochondria. Studies have shown that certain Chinese herbs significantly increase mitochondrial ATP (cell's energy source)! This is exciting because mitochondria are inherited from the mother, and these same herbs are often used in female fertility treatments!
Somatic (non-sex) cells are diploid, meaning that their chromosomes are arranged in pairs (23 pairs). Gametes (sex cells: sperm and eggs) are haploid and contain 22 autosome (single) chromosomes and 1 sex chromosome.
We all tend to think that genetics and its implications are imprinted in us from birth and cannot be changed, but how we live our life and what we do to be more healthy can have a huge impact on ourselves and future generations.
Epigenetics is the surrounding layer of information that decides if and when genes are expressed. Genes can be switched on and off at certain times in our life and in certain body tissues. Without being able to change the DNA sequence, you CAN improve your health by affecting the chemistry of the DNA (example is adding a methyl group - CH3).
How can you influence epigenetics?...through diet, exercise, environment, nutritional supplementation, acupuncture, herbs, and psychosocial therapies
HORMONES AND THE ENDOCRINE SYSTEM (ES)
A hormone is a substance produced in a special tissue, where it is released into the bloodstream, and travels to distant responsive cells (target tissue), where the hormone exerts its characteristic effects. The widespread capability of cells to make hormones explains the fascinating discoveries of hormones in unlikely places, such as gastrointestinal hormones in the brain, reproductive hormones in intestinal secretions, and the ability of cancers to unexpectedly make hormones. Hormones are chemical regulatory and signaling agents that provide a means of communication. Hormones have effects not only on distant sites, but also on local ones. Paracrine communication involves local diffusion of regulating substances from one cell to nearby cells. Autocrine communication involves the cell's production of regulating substances that act upon receptors within that same cell, on the surface of the cell membrane. Intracrine communication occurs when hormones bind to receptors inside the cell, usually the nuclear membrane receptors.
A hormone target tissue can respond to the hormone because it contains a specific receptor protein that, on binding to the hormone, will bind to a DNA enhancer site. The area that will initiate DNA action is called an enhancer region. The enhancer sites bind regulatory proteins that serve as signals to regulate gene expression. This is accomplished by either increasing or decreasing the binding of RNA polymerase (enzyme that produces RNA needed for transcription) in the promoter region (where protein synthesis occurs). Transcription is the synthesis of single-stranded messenger RNA from a gene (double-stranded DNA). Transcription factors are proteins that bind to regulatory elements in DNA (enhancers and promoters), thereby influencing gene expression.
Hormones can be broadly classified as either peptides (proteins) or steroids (lipids). Examples of peptide hormones include insulin and growth hormone (GH). Some peptide hormones have carbohydrate side chains, so they are called glycoprotein hormones, and these include luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH/thyrotropin). LH and FSH are also called gonadotropins. (Tropic hormones or "tropins" are those that influence another endocrine gland.) These hormones are considered to have low lipid solubility, which means that they cannot easily pass through the lipid bilayer of the target cell membrane. They are released by exocytosis, a sort of mechanism that looks like the cell is squeezing out a bubble along the cell's edge, and this "bubble" contains the peptide hormone. They then communicate with the target cell by joining with specific receptors on the target cell membrane, and then this action stimulates action of another chemical called a 2nd messenger, such as cyclic adenosine monophosphate (cyclic AMP), which triggers further actions that create the hormone's effect on the cell.
Steroid hormones are derived mostly from cholesterol, and these include estrogen, progesterone, testosterone, and cortisol. These have a high lipid solubility, so they can easily cross the cell membranes. The adrenal cortex produces cortisol and a portion of androgens. The sex steroids are a subset of steroid hormones, and include estrogens, progesterone, and androgens, and are produced by the ovary. Estrogen is really a collective term referring to a group of hormones that includes estrone (E1), estradiol (E2), and estriol (E3). The most powerful of these is estradiol (E2), and this can sometimes be harmful in excessive amounts. Estriol (E3) is the most benign and protective form of estrogen, as it protects the heart and bones of women. Androgens include testosterone and its precursors androstenedione and androstenediol.
Functionally, hormones are classified according to their effects. They can have kinetic effects, affecting glandular secretion or muscle contraction. They can have metabolic effects, affecting biochemical reaction rates. They can have morphogenetic effects, affecting growth and differentiation. They can also have behavioral effects.
The hypothalamus and pituitary glands are located in the brain. The hypothalamus and the hormones it secretes are an important link between the nervous system and the endocrine system. The hypothalamus receives input from other regions of the brain, as well as sensory signals from internal organs. Environmental changes such as stress, emotions, and pain affect hypothalamic activity. In turn, the hypothalamus controls the autonomic nervous system (ANS) and, therefore, regulates functions such as body temperature, thirst, hunger, heart rate, respiration, and emotional reactions. And so, it is a regulatory center of the ANS...but its cells synthesize many different hormones, and so do the cells of the pituitary gland.
Table 1. Hypothalamic hormones and their effects
| Thyrotropin-releasing hormone (TRH) or Prolactin-releasing hormone (PRH) | Stimulates Thyroid-Stimulating Hormone (TSH) and Prolactin (PRL) release from anterior lobe of pituitary gland |
| Dopamine | Inhibits prolactin release from anterior lobe of pituitary gland |
| Growth Hormone-Releasing Hormone (GHRH) | Stimulates growth hormone (GH) release from anterior lobe of pituitary gland |
| Somatostatin | Inhibits GH and TSH release from anterior lobe of pituitary gland |
| Corticotropin-Releasing Hormone (CRH) | Stimulates adrenocorticotropic hormone (ACTH) release from anterior lobe of pituitary gland |
| Vasopressin (Anti-Diuretic Hormone/ADH)- (also stored in the posterior lobe of pituitary gland) | Affects kidney function so that the body retains water (decreases urine production) |
| Oxytocin (also stored in the posterior lobe of pituitary gland) | Stimulates uterine contraction and lactation |
| Gonadotropin-Releasing Hormone (GnRH) | Stimulates FSH and LH release from anterior lobe of pituitary gland |
The pituitary gland, also known as the hypophysis, consists primarily of 2 lobes: anterior lobe is called the adenohypophysis; and posterior lobe is called the neurohypophysis.
Table 2. Pituitary hormones and their effects
| Human Growth Hormone (HGH)/Somatotropin | Stimulates liver, muscle, bone, and other tissues to secrete insulin-like growth factors (IGFs), which promote body cell growth, tissue repair, lipolysis, and increased blood glucose concentration |
| Melanocyte-Stimulating Hormone (MSH) | Promotes skin pigmentation |
| Adrenocorticotropic Hormone (ACTH)/corticotropin | Stimulates secretion of glucocorticoids (mainly cortisol) by adrenal cortex of adrenal glands (located just above the kidneys) |
| Prolactin (PRL) | Promotes milk secretion by mammary glands; elevated PRH can cause amenorrhea |
| Thyroid-Stimulating Hormone (TSH)/thyrotropin | Stimulates thyroid gland to secrete thyroid hormones |
| Luteinizing Hormone (LH) | Women: stimulates ovulation, and formation of corpus luteum, which secretes estrogens, progesterone, relaxin, and inhibin Men: stimulates Leydig cells in testes to produce testosterone |
| Follicle-Stimulating Hormone (FSH) | Women: develops oocytes (egg cells) from primordial follicles within the ovaries, and induces ovarian secretion of estrogens Men: stimulates Sertoli cells of testes to produce sperm |
Sex steroid hormones are produced by the gonads (ovaries and testes), the organs that contain gametes (eggs and sperm). During pregnancy, a gonad may start to become a testis at 6-9 gestational weeks. A gene located on the Y chromosome produces the factor that determines this: the testes-determining factor (TDF). Absent TDF, the fetus will develop ovaries, uterus, and fallopian tubes to become female. If TDF is present, the function of Anti-Mullerian Hormone (AMH) is to halt the formation of these female reproductive structures. However, AMH in women is detected in primordial follicles and reaches peak values in antral follicles. Its function here is to inhibit follicle growth, thereby allowing the appearance of the dominant follicle. Since AMH levels indicate the number of growing follicles, it is used as a measure of ovarian age and fertility.
REPRODUCTION - FEMALE
The Ovaries
The ovaries, a pair of glands that are about the size and shape of almonds, are held in place by a series of ligaments (the broad, ovarian, and suspensory ligaments). The ovaries are attached to the uterus via these ligaments. Each ovary consists of 3 major portions: the outer cortex, the central medulla, and the hilum, where nerves and blood vessels enter. The ovaries have the primary responsibility of releasing eggs, which are embedded in the inner part of the cortex, and producing the steroid hormones estradiol (E2) and progesterone (P4). The most important functions of progesterone are to prepare the uterus for pregnancy and to maintain a healthy balance with estradiol (E2), thereby protecting the body against the potentially harmful effects of excess E2.
Estrogen is responsible for producing female characteristics in the womb and in puberty. We tend to associate menopause with the decline of estrogen production, but it is often preceded by a dramatic decline in progesterone. Those who use hormone replacement of either of these hormones should proceed with extreme caution and careful monitoring.
Many women are concerned with FSH levels > 10. But what exactly is a follicle? A follicle refers to a small group of cells containing a cavity in which another structure grows. Hair follicles grow hair, and ovarian follicles contain haploid oocytes (ova, also known as "eggs"). We are told that we are born with a set number of eggs, and there is nothing we can do to increase this number. This is true in terms of quantity of primordial (immature) follicles, but we CAN change the quality of the eggs we have left. For more detailed molecular information on how, please scroll up to the "Genetics and Epigenetics" section of this page.
Since folliculogenesis, or the time required to go from a primordial (immature) follicle to a ripe egg at ovulation, takes just over a year (or 13 menstrual cycles), we can surely try our best improve egg quality through Chinese medicine, nutrition, exercise, stress reduction, and other therapies. In particular, the last 3 months of this process is crucial because this is when the follicle experiences the fastest growth, going from the pre-antral stage to ovulation. This is why you should not be discouraged if it takes longer than 3 months to get pregnant, after improving your diet and lifestyle and/or receiving acupuncture and herbal treatments.
Before birth, the ovary contains about 6 - 7 million follicles. By the onset of puberty, 300,000 - 500,000 follicles remain. During the next 40 years of reproductive life, 400 - 500 will be selected to ovulate. In the last 10-15 years before menopause, follicular loss accelerates. This process of follicular degeneration and resorption is called atresia. This loss corresponds with increased FSH, and decreased E2, inhibin-B, and insulin-like growth factor-1 (IGF-1). Starting from resting follicles, some primordial follicles are recruited to become biologically active about a year before ovulation. About 150 days later, the .03-mm follicle is chosen to double in size to become the primary follicle, about .1 mm in diameter. The formation of a primary follicle is marked by a change in the surrounding cells to become granulosa (support) cells. The primary follicle becomes the secondary follicle (.2 mm) in about 120 days. This secondary (pre-antral) follicle's granulosa cells have the ability to make steroid hormones. Going from the secondary (pre-antral) follicle to ovulation takes about 85 days, or 3 menstrual cycles. In the transformation from secondary (pre-antral) to tertiary (antral/Graafian) stage, the follicles are divided into 5 classes, according to size. Class 1 follicles are .2 mm, Class 5 follicles are 5 mm, and the others are in between that range. In the next stage, there are 3 more classes: Class 6 follicles are 10 mm, Class 7 follicles are 16 mm, and Class 8 (pre-ovulatory) follicles are approximately 20 mm in diameter, and contains theca cells, which help to produce E2 for nearby granulosa cells by producing androstenedione, an androgen that is an E2 precursor. The term recruitment refers to the growth of antral follicles in response to FSH.
Table 3. Menstrual cycle events for a 28-day cycle
| Day and Events | FSH | LH | E2 | P4 |
| 1 - 5: Uterine lining is no longer maintained due to low E2 and P4, so flow starts Pituitary gland starts to make FSH and LH to stimulate growth of new follicles in ovary | sl. high | sl. high | very low | very low |
| 7: One follicle outgrows the others and produces lots of E2 | low | low | rising | very low |
| 7 - 12: High E2 stimulates growth of uterine lining, and production of fertile mucus by glands in cervix | low | rising | peak | low |
| 12 - 13: High E2 encourages pituitary gland to release more LH | sl. high | peak | high | low |
| 14: Ovulation! Egg is released when enzymes cause follicle wall to break, and prostaglandins stimulate egg's expulsion | low | drop | sl. low | rising |
| 15 - 25: Corpus luteum forms from the empty follicle and produces primarily P4 (and some E2), which stimulates endometrium to secrete nutrients, and inhibits pituitary release of FSH and LH | low | low | sl. low | peak |
| 25 - 28: Corpus luteum dies, E2 and P4 drop, causing Day 1 - 5 events to occur in next cycle | low | low | low | low |
For a graphical depiction of the menstrual cycle, and numerical reference values of all reproductive hormones, please refer to Fertility Plus
The Uterus, Fallopian Tubes, Cervix, and Vagina
The uterus is a complex endocrine organ with multiple layers. One end of the uterus, the cervix, opens into the vagina. The other ends are connected to the Fallopian (uterine) tubes (oviducts).
The innermost layer is the endometrium, the outermost layer is the perimetrium, and in between lies the myometrium, the thickest layer, consisting of smooth muscle. The 2 uterine arteries that supply the uterus are branches of the internal iliac arteries. As these arteries branch further, the ends are called the spiral arteries (end arteries). It is the spiral artery segment that is sensitive to hormonal changes. The endometrium is a thin, yet dense, tissue, and and as much as 2/3 of it is lost during menstruation. The more rapid the tissue loss, the shorter the duration of flow. Heavier flow and greater blood loss implies delayed or incomplete shedding. The upper 2/3 of the endometrium is called the functionalis layer, and the lower 1/3 is the basalis layer. The functionalis layer lines the uterine cavity, is shed during menstruation, and prepares for blastocyst (early embryo) implantation, and the basalis, which has many estrogen receptors, provides regeneration of tissue following menstrual loss. In ovulation, the egg is released from the follicle in the ovary, and then travels down the oviduct to the uterus. Fertilization must occur within 12-24 hours of ovulation, and this occurs in the oviduct. When pregnancy occurs, the endometrium is referred to as the decidua, and this forms the maternal part of the placenta. If the egg is not fertilized, progesterone levels decline, leading to prostaglandin (PG) release, which causes the uterine spiral arterioles to constrict, killing uterine tissue cells. Menstruation involves 30-80 mL of blood loss.
In summary, the phases of the menstrual cycle are: 1- menses; 2 - proliferative (pre-ovulatory); 3- ovulation; 4- luteal (the 2nd week of the luteal phase is called the secretory phase). The time of menses and the week after is also called the follicular phase, due to follicle growth at this time.
The Fallopian tubes (salpinges) consist of the isthmus, connecting them to the uterus; the ampulla, the site of fertilization; and the fimbriae, the finger-like projections that catch the egg from the ovary at ovulation. The egg then resides in the ampulla within 2-3 minutes, and then spends about 80 hours in the tube. The majority of pregnancies occur when intercourse takes place within the 3-day interval before ovulation.
REPRODUCTION - MALE
Sertoli cells - located in the seminiferous tubules of the testes (testicles); activated by Follicle-Stimulating Hormone (FSH); function to nurture the developing cells that make sperm
Leydig cells - located adjacent to the seminiferous tubules of the testes; activated by Luteinizing Hormone (LH); function to produce testosterone
Fertilization - It takes more than just one sperm!
There is an average of 200-300 million sperm deposited into the vagina, but only a few hundred (at most) get close to the egg. Many are expelled from the vaginal orifice, and some are digested by vaginal enzymes and phagocytosis in the reproductive tract. But the cervix does act as a reservoir, supplying sperm for up to 3 - 5 days.
Sources:
Speroff & Fritz. Clinical Gynecologic Endocrinology and Infertility, 7th edition.
Haig & Kristal. The Nutrition Solution: A guide to your metabolic type.
Lyttleton, Jane. Treatment of Infertility with Chinese Medicine, 2004.