Female Reproduction PDF

Chapter 22: Female Reproductions Intro ○ Modern genetics and experimental embryology make it clear that, in most species of mammals, the multiple differences between the male and female depend primarily on a single chromosome (the Y chromosome) and a single pair of endocrine structures, namely the t...

Chapter 22: Female Reproductions Intro ○ Modern genetics and experimental embryology make it clear that, in most species of mammals, the multiple differences between the male and female depend primarily on a single chromosome (the Y chromosome) and a single pair of endocrine structures, namely the testes in the male and ovaries in the female ○ The differentiation of the primitive gonads into the testes or ovaries in utero is genetically determined in humans, but the formation of male genitalia depends on the presence of a functional, secreting testis; in the absence of testicular tissue, development is female ○ Evidence indicates that male sexual behavior and in some species, the male pattern of gonadotropin secretion are due to the action of male hormones on the brain in early development ○ After birth, the gonads remain quiescent until adolescence, when they are activated by the gonadotropins from the anterior pituitary ○ Hormones secreted by the gonads at this time cause the appearance of features typical of an adult male or female and the onset of the sexual cycle in the females ○ In human females, ovarian function regresses after a number of years and sexual cycles cease (menopause) ○ In males, gonadal function slowly declines with advancing age, but the ability to produce viable gametes persists. Sex Chromatin ○ Soon after cell division has started during embryonic development, one of the two X chromosomes of the somatic cells in normal females becomes functionally inactive ○ In abnormal individuals with more than 2 X chromosomes, only one remains active ○ The process that is normally responsible for inactivation in an X-inactivation center in the chromosome, probably via the transactivating factor CTCF (from CCCTC binding factor), which is also induced during gene imprinting. ○ However, the details of the inactivation process are all still incompletely understood ○ The choice of which X chromosome remains active is random, so normally one X chromosome remains active in approximately half of the cells and the other X chromosome is active in the other half ○ The selection persists through subsequent divisions of these cells, and consequently some of the somatic cells in adult females contain an active X chromosome of paternal origin and some contain an active X chromosome of maternal origin Puberty ○ A burst of testosterone secretion occurs in male fetuses before birth ○ In the neonatal period there is another burst, with unknown function, but thereafter the Leydig cells become quiescent ○ There follows in all mammals a period in which the gonads of both sexes are quiescent until they are activated by gonadotropins from the pituitary to bring about the final maturation of the reproductive system ○ This period of final maturation is known as adolescence ○ It is often called puberty, although puberty, strictly defined, is the period when the endocrine and gametogenic functions of the gonads have first developed to the point where reproduction is possible. ○ In girls, the first event is thelarche, the development of breasts, followed by pubarch, the development of axillary and pubic hair, and then menarche, the first menstrual period ○ Initial menstrual periods are generally anovulatory, and regular ovulation appears about a year later ○ In contrast to the situation in adulthood, removal of the gonads during the period from soon after birth to puberty causes only a small increase in gonadotropin secretion, so gonadotropin secretion is not being held in check by the gonadal hormones ○ In children between the ages of 7 and 10, a slow increase in estrogen and androgen secretion precede the more rapid rise in the early teens ○ The age at the time of puberty is variable ○ In Europe and the US, it has been declining at the rate of 1-3 months per decade for more than 175 years. In the US in recent years, puberty generally occurs between 8 and 13 in girls and 9 and 14 in boys ○ Another event that occurs in humans at the time of puberty is an increase in the secretion of adrenal androgens ○ This onset of this increase is called adrenarche ○ It occurs at age 8-10 years in girls and age 10-12 in boys ○ Dehydroepiandrosterone (DHEA) values peak at about age 25 in women and slightly later than that in men ○ They then decline slowly to low values in old age. The rise appears to be due to an increase in the activity of 17a-hydroxylase The female reproductive system: The Menstrual cycle ○ The reproductive system of women, unlike that of men, shows regular cyclic changes that teleologically may be regards as periodic preparations for fertilization and pregnancy ○ In humans and other primates, the cycle is a menstrual cycle and its more conspicuous feature is the periodic vaginal bleeding that occurs with the shedding of the uterine mucosa (menstruation) ○ The length of the cycle is notoriously variable in women, but an average figure is 28 days from the start of one menstrual period to the start of th next ○ By common usage, the days of the cycle are identified by number, starting with the first day of menstruation Ovarian cycle ○ From the time of birth, there are many primordial follicles under the ovarian capsule ○ Each contains an immature ovum ○ At the start of each cycle, several of these follicle enlarge and a cavity forms around the ovum (antrum formulation) ○ This cavity is filled with follicular fluid ○ In humans, usually one of the follicles in one ovary starts to grow rapidly on about 6th day and becomes dominant follicle, while the others regress, forming atretic follicles ○ The atretic process involves apoptosis ○ It is uncertain how one follicle is selected to be the dominant follicle in this follicular phase of the menstrual cycle, but it seems to be related to the ability of the follicle to secrete estrogen inside it that is needed for final maturation ○ When women are given human pituitary gonadotropin preparations by injections, many follicles develop simultaneously ○ The follicle that ruptures at the time of ovulation promptly fills with blood, forming what is sometimes called a corpus hemorrhagicum ○ Minor bleeding from the follicle may cause peritoneal irritation and fleeting lower abdominal pain (“Mittelschmerz”) ○ The granulosa and theca cells of the follicle linding promptly begin to proliferate, and the clotted blood is rapidly replaced with yellowish, lipid rich luteal cells, forming the corpus luteum ○ This initiates the luteal phase of the menstrual cycle, during which the luteal cells secrete estrogen and progesterone ○ Growth of the corpus luteum depends on its developing an adequate blood supply, and there is evidence that vascular endothelial growth (VEGF) is essential for this process Uterine Cycle ○ At the end of menstruation, all but the deep layers of the endometrium have sloughed ○ A new endometrium then regrows under the influence of estrogens from the developing follicle ○ The endometrium increases rapidly in thickness from the 5th to the 14th days of the menstrual cycle ○ As the thickness increases, the uterine glands are drawn out so that they lengthen, but they do not become convoluted or secrete to any degree ○ The endometrial changes are called proliferative and this part of the menstrual cycle is sometimes called the proliferative phase ○ It is also called the preovulatory or follicular phase of the cycle ○ After ovulation, the endometrium becomes highly vascularized and slightly edematous under the influence of estrogen and progesterone from the corpus luteum ○ The glands become coiled and tortuous and they begin to secrete a clear fluid ○ Consequently, this phase of the cycle is called the secretory or luteal phase. ○ Late in the luteal phase, the endometrium, like the anterior pituitary, produces prolactin, but the function of this endometrial prolactin is unknown. Vaginal cycle ○ Under the influence of estrogen, the vaginal epithelium becomes cornified, and cornified epithelial cells can be identified in the vaginal smear ○ Under the influence of progesterone, a thick mucus is secreted and the epithelium proliferates and becomes infiltrated with leukocytes ○ The cyclical changes in the vaginal smear in rats are relatively marked ○ These changes in humans species are similar but not so clearcut Cyclical changes in the breasts ○ Although lactation normally does not occur until the end of pregnancy, cyclical changes take place in the breasts during the menstrual cycle ○ Estrogens cause proliferation of mammary ducts, whereas progesterone causes growth of lobules and alveoli ○ The breast swelling, tenderness and pain experienced by many women during the 10 days preceding menstruation are probably due to distention of the ducts, hyperemia and edema of the interstitial tissue of the breast ○ All these changes regress, along with the symptoms, during menstruation Indicators of ovulation ○ Knowing when during the menstrual cycle ovulation occurs is important in increasing fertility or conversely in family planning ○ A convenient and reasonable reliable indicator of the time of ovulation is a change– usually a rise– in the basal body temperature ○ The rise starts 1-2 days after ovulation ○ Women interested in obtaining an accurate temperature chart should use a digital thermometer and take their temperatures (oral or rectal) in the morning before getting out of bed ○ The cause of temp change at the time of ovulation is probably the increase in progesterone secretion, since progesterone is thermogenic Menopause ○ The loss of ovarian function causes many symptoms such as sensations of warmth spreading from the trunk to the face (hot flushes; also called hot flashes) and night sweats ○ In addition, the onset of menopause increases the risk of many diseases such as osteoporosis, ischemic heart disease and renal disease ○ Hot flushes are said to occur in 75% of menopausal women and may continue intermittently for as long as 40 years. ○ They also occur when early menopause is produced by bilateral ovariectomy and they are prevented by estrogen treatment. In addition, they occur after castration in men ○ Their cause is unknown Secretion ○ Under the influence of estrogens, the muscle becomes more active and excitable and action potentials in the individual fibers become more frequent ○ The “estrogen dominate” uterus is also more sensitive to oxytocin ○ Chronic treatment with estrogens causes the endometrium to hypertrophy ○ When estrogen therapy is discontinued, sloughing takes place with withdrawal bleeding ○ Some “breakthrough” bleeding may occur during treatment when estrogens are given for a long period ○ Prolonged exposure to estrogen alone (unopposed by progesterone) has been indicated as a risk factor in the development of endometrial cancer Effects on the breasts ○ Estrogens produce duct growth in the breasts and are largely responsible for breast enlargement at puberty in girls; they have been called the growth hormones of the breast ○ They are responsible for the pigmentation of the areolas, although pigmentation usually becomes more intense during the first pregnancy that it does at puberty Actions ○ The principle target organs of progesterone are the uterus, the breasts, and the brain ○ Progesterone is responsible for the progestation changes in the endometrium and the cyclical changes in the cervix and vagina ○ It has an antiestrogenic effect on the myometrial cells, decreasing their excitability, their sensitivity to oxytocin and their spontaneous electrical activity while increasing their membrane potential. It also decreases the number of estrogen receptors in the endometrium and increases the rate of conversion of 17b Estradiol to less active estrogens ○ In the breast, progesterone stimulates the development of lobules and alveoli ○ It induces differentiation of estrogen prepared ductal tissue and supports the secretory function of the breast during lactation Abnormalities of ovarian function ○ Menstrual abnormalities Some women who are infertile have anovulatory cycles; they fail to ovulate but have menstrual periods at fairley regular intervals Anovulatory cycles are the rule for the first 1-2 years after menarche and again before the menopause Amenorrhea is the absence of menstrual periods If menstrual bleeding has never occurred, the condition is called primary amenorrhea Some women with primary amenorrhea have small breasts and other signs of failure to mature sexually Cessation of cycles in a woman with previously normal periods is called secondary amenorrhea The most common cause of second amenorrhea is pregnancy, and the old clinical maxim that “secondary amenorrhea should be considered due to pregnancy until proven otherwise” has considerable merit Other causes of amenorrhea include emotional stimuli and changes in the environment, hypothalamic diseases, pituitary disorders, primary ovarian disorders, and various systemic diseases Metrorrhagia is bleeding from the uterus between periods, and oligomenorrhea is refused frequency of periods Dysmenorrhea is painful menstruation The severe menstrual cramps that are common in young women quite often disappear after the first pregnancy Most of the symptoms of dysmenorrhea are due to accumulation of prostaglandins in the uterus, and symptomatic relief has been obtained by treatment with inhibitors of prostaglandin synthesis Some women develop symptoms such as irritability, bloating, edema, decreased ability to concentrate, depression, headache, and constipation during the last 7-10 days of their menstrual cycles These symptoms of the premenstrual syndrome (PMS) has been attributed to salt and water retention However it seems unlikely that this or any of the other hormonal alterations that occur in the late luteal phase are responsible because the time, course, and severity of the symptoms are not modified if the luteal phase is terminated early and menstruation produced by administration of mifepristone The antidepressant fluoxetine, which is a serotonin reuptake inhibitor, and the benzodiazepine alprazolam produce symptomatic relief, and so fo GnRH releasing agonists in doses that suppress the pituitary-ovarian axis How these diverse clinical observations for together to produce a picture of pathophysiology of PMS is still unknown Pregnancy ○ Fertilization and implantation In humans, fertilization of the ovum by the sperm usually occurs in the ampulla of the uterine tube Fertilization involves: 1. Chemoattraction of the sperm to the ovum by substances produced by the ovum 2. Adherence to the zona pellucida, the membranous structure surrounding the ovum 3. Penetration of the zona pellucida and the acrosome reaction 4. Adherence of the sperm head to the cell membrane of the ovum with breakdown of the area of fusion and release of the sperm nucleus into the cytoplasm of the ovum Millions of sperm are deposited in the vagina during intercourse Eventually 50-100 sperm reach the ovum, and many of them contact the zona pellucida Initiation of lactation after delivery ○ The breasts enlarge during pregnancy in response to high circulating levels of estrogen, progesterone, prolactin and possibly hCG ○ Some milk is secreted into the ducts as early as the 5th month, but the amounts are small compared with the surge of milk secretion that follows delivery ○ In most animals, milk is secreted within an hour of delivery, but in women, it taks 1-3 days for the milk to “come in” ○ After expulsion of the placenta at parturition, the levels of circulating estrogens and progesterone abrupting decline ○ The drop in circulating estrogen initiates lactation ○ Prolactin and estrogen synergize in producing breast growth, but estrogen antagonizes the milk producing effect of prolactin on the breast ○ Indeed, in women who do not wish to breastfeed their babies, estrogens may be administered to stop lactation ○ Suckling not only evokes oxytocin release and milk ejection, it also maintains and augments the secretion of milk because of the stimulation of prolactin secretion it produces Gynecomastia ○ Breast development in male is called gynecomastia ○ It may be unilateral but is more commonly bilateral ○ It is common in newborns because of transplacental passage of maternal estrogens (occuring in about 75%) ○ It also occurs in a mild, transient from 70% of normal boys at the type of puberty and many men over the age of 50 ○ It occurs in androgen resistance ○ It is a complication of estrogen therapy and is seen in patients with estrogen secreting tumors ○ It is found in a wide variety of seemingly unrelated conditions, including eunuchoidism, hyperthyroidism and cirrhosis of the liver ○ Digitalis can produce it, apparently because cardiac glycosides are weakly estrogenic ○ It can also be caused by many other drugs ○ It has been seen in malnourished prisoners of war but only after they were liberated and eating an adequate diet ○ A feature common to many and perhaps all cases of gynecomastia is an increase in the plasma estrogen: androgen ratio due to either increased circulating estrogens or decreased circulating androgens Hormones and cancer ○ About 35% of carcinomas of the breast in women of childbearing age are estrogen dependent; their continued growth depends on the presence of estrogen in the circulation ○ The tumors are not cured by decreasing estrogen secretion, but symptoms are dramatically relieved and tumor regresses for months or years before recurring ○ Women with estrogen dependent tumors often have a remission when their ovaries are removed ○ Inhibition of the action of estrogens with tamoxifen also produces remissions, and inhibition of estrogen formation with drugs that inhibit aromatase is even more effective