1 Reproduction Lecture Spring 2009 Slide #2: The term gonads refer to the sex organs. In the male, these are the testes, and the in the female, the ovary. The produce sex cells, or gametes. The male gamete is sperm, and the female gamete is the oocyte, or egg. The cell produced when the sperm fertilizes the egg is called a zygote. It is the first cell of the new individual. Humans have 23 pairs of chromosomes (46), one pair from Mom and one from Dad. We are diploid. 22 of these pairs are called autosomes, and code for general traits. 1 pair of these chromosomes are sex chromosomes. If you are female, your sex chromosomes are XX. If you are male, they are XY. The image on this slide is called a karyotype and is made from metaphase chromosomes. Is this karyotype from a male or female? Slide #3: Because females have 2 X chromosomes, one must be silenced so that a cell doesn t receive conflicting information. The silenced X is condensed and tied to the nuclear envelope by protein threads. It is called a Barr Body. Which of the two X chromosomes is inactivated in a given cell is random. This occurs at approximately the 16 th day of fetal development. Once a particular cell silences an X, the same X will be silent in every cell arising from that cell. In females, then, all of our cells are not expressing the same X we are chimeras! Slide #4: This has an implication for identical twins. If the twins are female, they may have different patterns of expression depending on which X is silenced in which of their cells. This results in the development of genetic mosaics, very much like a calico kitten. Slide #5: Formation of ovaries and testes; Structures are the same for both sexes for the first 40 days. Gamete stem cells move to the gonads from the yolk sac. If an embryo has a Y chromosome, it contains the SRY gene. This gene produces a protein called the testis determining factor or TDF. Under the influence of TDF, the seminferous tubules develop, and spermatogenesis begins with the development of germinal cells (or sperm) and Sertoli cells. The Leydig cells begin to secrete testosterone at about 8 weeks post-conception. Testosterone production peaks at around weeks, and then begins to decline. The scrotum descends near birth. If it does not, it is referred to as cryptorchidism and the condition is surgically corrected, as sperm development is impaired at higher temperatures. Slide #6: Development of accessory sex organs (male): The development of male accessory organs is complex. After the SRY gene is expressed, and TDF is produced, the testes develop. In the meanwhile, the placenta produces human chorionic gonadotropin. This hormone signals to the corpus luteum to continue to produce hormones to maintain the pregnancy until the placenta can take over completely. HCG is the hormone that is detected by pregnancy tests. It is also the hormone that stimulates the production of testosterone by the Leydig cells. Testosterone then stimulates male internal development of the Woolfian ducts and regression of the Mullerian ducts by stimulating the Sertoli cells to produce Mullerian inhibitory hormone. Slide #7: Development of accessory sex organs (female); If an embryo is female, she is genetically XX, and therefore has no SRY gene. The Woolfian ducts to not develop, and the mullerian ducts do, as do the ovaries. Female, then, is the default setting. Slide #8: This image shows the undifferentiated initial structure found in both males and females for the first 40 days of development. Male and female differentiation is reviewed in the two lower structures. It is easy to see how closely related the internal structures are when looking at these images. Slide #9: This set of images includes the development of external genitalia, shown at the bottom of the slide. Note that the clitoris in the female, and the penis in the male are derived from the same structure.
2 Slide #10: Disorders of sexual development: This ultrasound is of an hermaphroditic child with both ovaries and testes present. These individuals have both XX and a partial Y. Most common karyotypes include 47XXY, 46XX/46XY, or 46XX/47XXY. External genitalia are often ambiguous. This can result from several unusual circumstances, such as an ovum dividing to form two haploid ova, which are then subsequently fertilized. The resulting zygotes then fuse again. In some cases, a single ovum can be fertilized by two sperm (one set of chromosomes is lost ), or two different ova can each be fertilized, resulting in one male and one female zygote that then fuse. They are also considered mosaic. Slide #11: Pseudohermaphroditism: In the female, the individual is genetically XX, but the external genitalia are ambiguous (not clearly differentiated along female lines). In the male, a Y chromosome is present, but the genital ducts or external genitalia are not completely differentiated along male lines. They may, in fact, be completely female. This is most often the result of genetic defects in production of male sex hormones (androgens), resulting in defective development of secondary male sex characteristics in the embryo (virilization). Sometimes, the androgens are being produced, but the receptor is ignoring the androgens, a condition known as androgen insensitivity syndrome. Slide #12: Abnormal development; This chart compares the characteristics of individuals with a variety of genotypes. It is self explanatory. Slide #13: Turner s Syndrome: Individuals with this genetic abnormality have only one sex chromosome, an X. Therefore, their genotype is written as XO. It is the most common sexual abnormality of females. Individuals with Turner s syndrome are female in appearance, short in stature, sexually infantilism (delayed or arrested sexual development), and may have several other somatic abnormalities, such as heart disease, hypothyroidism, malformed kidneys, and skeletal abnormalities. Slide #14: Klinefelter s syndrome XXY. This is the most common sex chromosome disorder, effecting approximately 1of 1000 males. This image shows the physical characteristics. They include hypogonadism, infertility, gynecomastia (breast tissue), female pubic hair pattern, narrower shoulders than common in men and long legs Slide #15: Endocrine regulation: During early development, testes produce testosterone in male embryos in order to ensure that male sex characteristics will develop. The testes are inactive at birth. In the female, ovaries mature in the 3 rd trimester, but are also inactive at birth. Before puberty, hormones in males and females are essentially the same. At puberty, as the brain matures, there is an increase in the secretion of tropic hormones which triggers an increase in sex hormone production. Slide #16: Hypothalamus, pituitary, gonads; Gonadotropic releasing hormone must be produced continuously by the hypothalamus. In order to prevent downregulation, it is released by pulsatile secretion. The anterior pituitary responds by releasing follicle stimulating hormone (FSH) and leutinizing hormone (LH). These hormones regulate spermatogenesis (the development of sperm) and oogenesis (the development of oocytes). They also stimulate hormone secretion by the gonads, and maintain the structure of the gonads. Levels are maintained by negative feedback inhibition of GnRH, and the tropic hormones (FSH,LH) produced. Inhibin is also produced by the Sertoli cells and the ovarian follicles. This inhibits follicle stimulating hormone, but not leutinizing hormone, allowing the production of sex hormones separately from the production of gametes. Male hormone secretion begins again at puberty and continues until death.. In the female, it begins again at puberty but stops at around age 50 (menopause). Male hormone levels are relatively constant, while female hormones level fluctuate throughout the monthly cycle. Slide #17: Onset of puberty: When puberty begins, first there is an increase in FSH, then in LH. This occurs by two mechanisms. In the first, there is an increase in the production of GnRH by
3 the hypothalamus commiserate with the maturation of the brain. In addition, there is decreased sensitivity of growth hormone (GH) to he negative feedback effects of sex steroids. These hormones are secreted in greatest quantities during sleep. As a result of the increase of FSH, secondary sex characteristics begin to develop, accompanied by a growth spurt. If an individual has high body fat and does not exercise regularly, the effects of body fat can effect the onset of puberty. These individuals will enter puberty before their normal weight colleagues. Male Reproductive System Slide #19: If you recall, the anterior pituitary produces two gonadotropic hormones, follicle stimulating hormone (FSH) and leutinizing hormone (LH). In the male reproductive system, the receptors for FSH are located only on the Sertoli cells, and binding to these receptors stimulates spermatogenesis. LH receptors are located only on the Leydig cells, and binding of LH to these receptors stimulates the production of testosterone. Slide #20: Gonadotropic hormone production is controlled by feedback inhibition. For LH, the testosterone that is produced goes back in a long loop of inhibition and inhibits the anterior pituitary. There are receptors in the brain for the testosterone. It can also be converted into other hormones, such as estradiol. These are all structurally related. Throughout the life of a man, testosterone and inhibin production insure a relatively constant secretion. However, there is a gradual decline in testosterone production in men over 50. This often results in the enlargement of the prostate gland. Clinically, this condition is treated first by providing oral testosterone. Slide 21: Testicular endocrine production: Testosterone has many effects on the body. It stimulates growth of muscle and other structures, it ensures the development of secondary sex characteristics, it increases the amount of hemoglobin that is synthesized, and oddly, it stimulates the closure of the epiphyseal plate. Testosterone can also be converted to estradiol (estrogen). The estradiol downregulates Leydig cell function, helping to regulate the amount of testosterone produced, in addition to the negative feedback inhibition mentioned in the previous slide. As with other hormones, levels of one hormone affect the levels of other hormones. Slide #22: Spermatogenesis: This slide shows the development of sperm. For each spermatogonium that divides, four viable sperm are produced. Note that the germ cells are near the outer edge of the seminiferous tubules and that the cells mature as they move toward the lumen. Sertoli cells, also called sustentacular or nursing cells, aid in the development of the sperm. The slide is otherwise self-explanatory. Slide #23: Role of Sertoli cells and hormonal control; Sertoli cells are located throughout the seminiferous tubules. In addition to their role in shaping the sperm by phagocytosis of excess cytoplasm, they also form part of the blood-testis barrier which prevents destruction of the developing sperm by the immune system, and they produce androgen binding protein, which helps to concentrate testosterone in the lumen of the seminiferous tubules so that the sperm are able to mature appropriately. FSH stimulates the development of sperm. Slide #24: Male accessory organs; Lists the pathway of the sperm through the male tubule system to the outside of the body. The epididymis is where sperm first develop the ability to swim. I refer to it as swim school. It is here that sperm also acquire a level of resistance to ph and to temperature changes. Remember that they must travel down the male urethra (a common passageway for urine) and into the hostile environment of the female reproductive system to reach the oocyte. They also develop an increased capacity to fertilize the oocyte while they are in the epididymis, but they are not fully capacitated until they have spent some time in the female reproductive tract. The epididymis is also a storage area for sperm. If the sperm are not ejaculated, they are eventually reabsorbed by the body. Slide #25: Image of the male reproductive system
4 Slide #26: Erection, emission, ejaculation; Recall from anatomy that the penis contains erectile tissue in the form of the corpora cavernosa and the corpus spongiosum. Erection is accomplished by spinal cord reflex under the direction of the parasympathetic nervous system. The PNS stimulation results in vasodilation of the arterioles with the help of Nitric Oxide. This causes the erectile tissue to flood with blood, and depresses the veins and obstructs them so that the erection can be maintained. Emission and ejaculation require the help of the sympathetic nervous system. Sympathetic nerves stimulate peristaltic waves over the tubes, contraction of the seminal vesicles and the prostate, and contraction of the muscle at the base of the penis. Semen is composed of the sperm, plus the secretions of the seminal vesicles and the prostate gland. An additional gland, the bulbourethral gland, secretes a clear liquid just before ejaculation that neutralizes the ph of the male urethra in order to protect the sperm. Slides 27-29: Vasectomy illustrations Female reproductive system Slide #31: Development of oocytes; Production of the oocytes in the female is completed by the time the fetus is 5 months gestation. By that time, 6-7 oogonia (germ cells) have been produced. By the end of gestation, meiosis I has been initiated, the oogonia are arrested in prophase I as primary oocytes, and only 2 million remain. These numbers continue to decline so that only about 3-400,000 oocytes remain by the time a female reaches puberty. Slide #32: Development of oocytes; In the ovary, oocytes are housed in follicles, a circle of cells with the oocyte in the middle. The primary oocytes are in primary follicles, which consist of a single, unstimulated layer of granulosa cells. If primary follicles are moved forward due to stimulation by FSH, they become secondary follicles, which consist of several layers of granulosa cells. They increase in size and vesicles begin to form between the oocyte and the granulosa cells. Eventually, the vesicles will fuse to form a space, or antrum. This is now called a Graafian follicle. Within the Graafian follicle, the primary oocyte completes meiosis I and becomes a secondary oocyte, which is arrested in metaphase II (the oocyte does not complete meiosis II unless it is fertilized!) Some of the granulosa cells become theca cells and produce androgens. The androgens are then converted to estrogens by the granulosa cells under the influence of FSH. Slide #33: Image showing division of the oocyte and development of the follicle. Slide #34: Image showing the structure of the follicle. Note the increasing layers of granulosa cells as the follicle matures. Slide #35: Histology slide of cat ovary showing developing follicles. Slide #36: Ovulation; Ovulation is defined as the release of the oocyte into the uterine tube. If fertilization does not occur, the oocyte is reabsorbed by atresia. When ovulation occurs, the secondary oocyte, zona pellucida, and corona radiata are all released. The zona pellucida is a layer surrounding the oocyte that hardens when sperm enter to prevent fertilization by more than one sperm. In addition, it is a species barrier so that only human sperm can fertilize human eggs. After release of the oocyte and accompanying structures, the corpus luteum remains behind. This structure now produces androgens and progesterones under the direction of leutinizing hormone. These hormones maintain the inner lining of the uterus until the embryo can implant and the placenta can take over hormone production to maintain the pregnancy. When the corpus luteum is no longer needed, it degenerates to become a corpus albicans. Slide #37: Ovarian phases; The female cycle is divided into several phases based on the changes in the ovary and the changes in the uterus. The ovarian phases include the follicular phase, ovulation, and luteal phase.
5 Slide #38: Ovarian phases; The follicular phase (the part of the cycle in which the ovarian follicle develops) occurs during the first 13 days of the menstrual cycle. Initially, hormones are at their lowest levels and the ovaries contain only primordial and primary follicles. Then about primary follicles move forward to become secondary follicles. One of these matures to become a Graafian follicle. FSH stimulates the granulosa cells to produce estradiol in increasing quantities. The FSH receptors on the granulosa cells are upregulated, making them more sensitive to FSH. A positive feedback loop is intiated which causes gonadotropic releasing hormone to be secreted with greater frequency from the hypothalamus. This also causes an increase in the LH levels. LH receptors are upregulated on the Graafian follicle, and ultimately, an LH surge triggers ovulation. Slide #39: Ovarian phases: Ovulation occurs on day 14 when a LH surge causes the Graafian follicle to rupture, expelling the 2 nd oocyte, aona pellucida, and corona radiata. Now, the corpus luteum takes over and the luteal phase begins (days 15-28). During this time, leutinizing hormone stimulates the development of the corpus luteum. Cervical mucus thickens and becomes sticky because of the production of progesterone (the hormone of pregnancy). At the end of the luteal phase, if there is no fertilization, then the corpus luteum degenerates due to the production of luteolysin by the uterus. This lead to a decrease in the amount of estrogen and progesterone secretion. Slide #40: Uterine phases of the menstrual cycle are the proliferative, secretory, and menstrual phases. These elucidate changes in the uterus during the menstrual cycle. Slide #41: Uterine phases: In the proliferative phase, increased secretions of estrogen lead to a thickening in the inner lining of the uterus (the stratum functional of the endometrium). Spiral arteries develop, and progesterone receptors on the endometrium are upregulated under the influence of estradiol. Slide #42: Uterine phases: in the secretory phase, uterine glands develop within the endometrium due to an increase in progesterone. The uterine glands are filled with glycogen to provide energy for the developing embryo. The endometrium becomes thickened and infiltrated with blood vessels. The sponginess makes it easier for the embryo to implant. Slide #43: Uterine phases; If fertilization and implantation do not occur, hormone levels decrease and the spiral arteries constrict. The vaginal epithelium becomes hardened (cornified) for renewed sexual activity, and the cervical mucus becomes thinner to allow for the penetration of sperm. Slide #44: Image compares the levels of pituitary hormones with the changes in the ovary (ovarian phases), ovarian hormone levels, and changes in the uterus during the uterine phases. Slide #45: Menopause: With age, control of the menstrual cycle by gonadotropic releasing hormone is lost. This results in a loss of remaining ovarian follicles. FSH and LH secretions are out of control as well with a loss of negative feedback inhibition. This results in the characteristic symptoms of menopause; hot flashes (vasomotor disturbances), urogenital atrophy, lack of lubrication, and increased risk of cardiovascular disease, osteoporosis, and atherosclerosis. Slide #46: HRT; The jury is still out on whether or not menopausal women should take hormone replacement therapy. The pro s and con s, as far as we know at this time, are presented on this slide. Slide #47: Sanning electron micrograph of sperm surrounding oocyte. Slide #48: The average ejaculum consists of 300 million sperm. The sperm must travel up into the fallopian tube in order to fertilize the oocyte. Approximately 100 sperm are able to get into the
6 fallopian tubes. Sperm must be in the female reproductive tract for at least 7 hours to be able to fertilize the oocyte. This is called capacitation. When fertilization occurs, the sperm penetrates the zona pellucida and the final meiotic division of the oocyte occurs. The two nuclei then fuse to produce a diploid zygote. The sperm contributes the centrosome (microtubule organizing center). Sperm can survive in the female reproductive tract for 3 days, and the oocyte lasts for one day after ovulation. Slide #49: After fertilization, the zygote begins to divide. This is called cleavage After about hours, the zygote has divided to form a ball of 8 cells called a morula. The morula travels down the fallopian tube toward the uterus and continues to divide. By the time it reaches the uterus (about 6 days), it has now become a ball of cells containing an inner mass, which will develop into the fetus, and the trophoblast cells, which will combine with cells from the Mom to become the placenta. Slide #50: A word about stem cells just read for your own interest Slide #51: Image of zygote 30 hours post fertilization Slide #52: When the blastula implants, the trophoblast cells produce human chorionic gonadotropin, the hormone detected by the rapid pregnancy tests. This hormone helps to maintain the corpus luteum so that the placenta has a chance to develop and become secretory, an it prevents menstruation, so that the pregnancy isn t aborted. By the 10 th week, HCG begins to decline and by 5-6 th week, the placenta becomes secretory. Slide #53: EPT Slide #54: Exchange of molecules; the placenta provides a safe barrier across which gases, waste, nutrients can pass. The placenta uses 1/3 of mom s oxygen and glucose, and the rate of protein synthesis in the placenta exceeds that of the livere. Slide #55: Fetal circulation. Follow the arrows Slide #56: Endocrine functions of the placenta: In addition to HCG, the placenta also produces chorionic somatotropin and growth hormone. This spares glucose for the fetus, and splits glucose, fatty acids to keep the sugar levels high. It also causes polyuria, which many people associate with pregnancy. Steroid hormones are also produced by the placenta. The production of these products requires both fetal and maternal precursors. This is called the fetal-placental unit. Slide #57: Labor and parturition. Uterine contractions are inititated by oxytocin and prostaglandins. Oxytocin receptors on the myometrium are upregulated by estrogen. Prostaglandin production is stimulated, and effects of oxytocin are increased without increasing the amount produced, just the sensitivity to oxytocin. Slide #58: Lactation; Insulin, cortisol, and thyroid hormones all contribute to the growth and development of the mammary glands. Progesterone stimulate the development of the mammary alveoli. Estrogen stimulates the proliferation of the tubules and ducts necessary to bring the milk to the surface. Prolactin inhibitory hormone (PIH) is produced in response for high estrogen levels. This allows the mammalian to develop during gestation while preventing lactation. Prolactin stimulates production of milk protein. Slide #59: Lactation; nursing initiates the neuroendocrine reflex that causes more prolactin to be produced and secreted. It also inhibits PIH and stimulates the release of prolactin releasing hormone ( PRH). In addition, nursing sitmulates oxytocin release (mechanical stimulus). This also causes the lactiferous ducts and uterus to contract. Nursing mothers decrease the size of their uterus faster than those who bottle feed their infants.
7 Slide #60-63: Image of changes in mammary glands; Last three slides describe the advantages of breast feeding..