Physio 24 - Reproduction PDF

PHYSIO 24 – Reproduction The reproductive system does not contribute to homeostasis and is not essential for survival of an individual, but it plays an important role in a person’s life. The manner in which people relate as sexual beings contributes in significant ways to psychosocial behavior. Re...

PHYSIO 24 – Reproduction The reproductive system does not contribute to homeostasis and is not essential for survival of an individual, but it plays an important role in a person’s life. The manner in which people relate as sexual beings contributes in significant ways to psychosocial behavior. Reproductive capability depends on intricate relationships among the hypothalamus, anterior pituitary, reproductive organs, and target cells of the sex hormones. In addition to these basic biological processes, sexual behavior and attitudes are deeply influenced by emotional factors and the sociocultural mores of the society in which the individual lives. UNIQUE SEX DETERMINATION AND SEXUAL DIFFERENTIATION BETWEEN MALES AND FEMALES The reproductive systems of males and females are markedly different: different roles in the reproductive process. The male and female reproductive systems are designed to enable union of genetic material from the two sexual partners (female system is equipped to house and nourish the offspring to the developmental point at which it can survive independently in the external environment). Growth and reproductive capability are strictly correlated as they have a cross-talk during adolescence. When the puberty begins (meaning the period in which the reproductive capability is acquired), there is the maturation of the reproductive system. Once the reproductive capability is acquired, growth ends as well. Hence the production of GH will decrease and the epiphyseal plates will close. The increase in secretion and the acquisition of a specific time course for the release of sex hormones will give the last kick of growth. Reproduction is a function which cannot be homeostatic as neither female nor male can perform reproduction alone. Individuals are different in their reproductive function. The sexual differentiation between males and females is significant different as they have different role in reproductive process. These 2 reproductive systems (male and female) are designed to enable the union of the genetic material between the 2 partners. Then it has to be chosen who has to carry on the process and who is equipped also to house a nourish during pregnancy and lactation. In animal world, generally, it is the female in charge of the nourishment of the offspring. 1.​ Overview The reproductive system is divided into primary reproductive organs, the gonads (ovaries and testis). They are called primary as they produce the gametes. Gametogenesis, so production of spermatozoa and eggs, is the distinguishing features of primary reproductive organs. The production of the gametes is rounded on the production of sex hormones. These hormones will drive all the process from precursor to final gametes in both sexes. Testosterone in males is the most relevant hormone and in female estrogen and progesterone play this role. Testosterone is also important in females as it allows to produce estrogens. The rest of the reproductive system is made by the reproductive tract which is a system of ducts specialized to transport or house the gametes after they are produced. -​ Accessory sex glands supportive secretions into reproductive tract (in females, the breasts are also considered accessory reproductive organs). These are important glands and their secretion is essential and not optional. -​ External genitalia the externally visible portions of the reproductive system The secondary sexual characteristics are the many external characteristics not directly involved in reproduction that distinguish males and females, such as body configuration and hair distribution. In some species, the secondary sexual characteristics are of great importance in courting and mating behavior. In animal world they allow to distinguish the male from the female and are involved in the attraction of the opposite sex. Males in animal world are often in charge of showing off to attract the females. 2.​ Overview of male reproductive tract In males the main role of the reproductive system has to roles ​ To produce sperm (spermatogenesis) ​ To deliver the sperm to the female. The reproductive system is made by testis (contained in scrotum) and they are the sperm-producing organs. Then there is the male reproductive tract made by the epididymis and the ductus deferens which transport and house the gametes. Another component are the accessory sex glands which are: seminal vesicles, prostate gland and bulbourethral glands. These accessory glands provide the bulk of the semen. The penis is involved in the deposition of the semen in the female. 3.​ Overview of the female reproductive organs Roles: ​ Production of ova (oogenesis) ​ Reception of sperm: configuration of this system is designs to be complementary to foster the reception of the sperm ​ Fertilization (conception): takes place in the female reproductive system ​ Gestation (pregnancy) ​ Parturition: ​ Lactation Ovaries are the ova-producing organs. Then there is the female reproductive tract made by the Oviduct or Fallopian Tube which are involved in the transport of ovum and it is the fertilization site. In the uterus the maintenance of the developing fetus takes place, including the formation of the placenta (organ of exchange between mother and fetus). Then the final portion is the cervix, the vagina, the labia minora and majora forming the way out for the fetus during parturition.  4.​ ≠ between genetic sex, gondal sex and phenotypic sex Sex of the embryo and fetus is genetically determined by the chromosomes present (XX or XY). This genetic sex depends on the chromosome found in the sperm. Curiously, the default line would be towards female. The embryo becomes a male as the Y chromosomes carries the SRY gene coding for the production of testis determining factor. The genetic sex is dependent on the combination of the 2 chromosomes. As the fetal life continues, there is the male determination only if there is the Y chromosome pushing, thanks to SRY, to the differentiation into testis. In the absence of SRY, spontaneously the female line is reached and spontaneously the ovaries will develop. Therefore, the line is towards the ovaries and only if there is the TDF (testis determining factor) the male line is taken. The gonadal sex is determined by the presence or absence of the SRY gene producing the TDF. During pregnancy, testis and ovaries start producing hormones. However, ovaries do not need to produce hormones to force the line as the female line is in default development in absence of androgens. It is the male which has to produce the masculinizing hormones including testosterone. Testosterone is already produced in prenatal life, and it is determinant in the development of the phenotypic sex. Thanks to this hormone there is the differentiation of the reproductive tract and external genitalia. The embryo would passively develop into female in absence of androgens. Masculinizing factors has to be added to the embryo to shift the line towards the male one. 5.​ Spermatogenesis Gonads in male are outside the abdominal cavity. In the embryo, the testes develop from the gonadal ridge located at the rear of the abdominal cavity. In the last months of fetal life, they begin a passing out of the abdominal cavity through the inguinal canal into the scrotum. Testosterone from the fetal testes induces descent of the testes into the scrotum (descent is usually complete by the 7° month of gestation, 98% of full-term baby boys). Testis are outside because of the temperature needed for spermatogenesis which is lower than the core temperature. The core temperature is around 37 degrees, but it is too much. The gonads has to go outside to obtain the optimal temperature. However, outside the temperature can vary a lot but being still located near the body there are some reflexes which allow further control of the temperature. There can be contraction of the scrotal muscle on exposure to a cold environment raises the scrotal sac to bring the testes closer to the warmer abdomen. By conduction the temperature of the core is transmitted to the testis. Relaxation of the muscles on exposure to heat permits the scrotal sac to become more pendulous, moving the testes farther from the warm core of the body Testosterone Testosterone is the main masculinizing androgen. It is a steroid hormone derived from a cholesterol precursor molecule. It is produced by the gonads and a portion of this testosterone is kept into the lumen of the seminiferous tubule where it is used for sperm production. A portion of this hormone diffuses in blood. This are the different possible precursors of testosterones. Filled arrows are the primary path for production, but it is even possible to go from pregnenolone to progesterone and then testosterone. The synthesis of testosterone in males takes place in Leydig cells placed in the interstitial matrix between the tubules, not in the wall of the seminiferous tubules where the Sertoli cells are present instead. Testosterone is produced for 95% in testis by Leydig cells from progesterone and pregnenolone and also diidrotestosterone is produced here for 20%. Another hormone produced in inhibin which is produced by Sertoli cells and it is present also in females. Via blood testosterone reaches liver, skin, adipose tissue and nervous tissue and it can be processed in these tissues towards oestrogens. Testis Testis perform a dual function: ​ Producing sperm ​ Secreting testosterone About 80% of the testicular mass consists of highly coiled seminiferous tubules, within which spermatogenesis takes place. The portions of the testes that produce sperm and secrete testosterone are structurally and functionally distinct. Function of sex homrones The sex hormones have a very targeted function, but being hormones part of the axis they also have a metabolic effect (apart from the structural and reproductive effect). It is possible to distinguish between reproductive functions and non-reproductive ones. The effect of this hormone also changes before and after birth. The effect on the reproductive system is to differentiate it in the prenatal life before birth. Then, it has an effect on sex specific tissue after birth (essential for spermatogenesis; -​ involved in maintenance of the reproductive tract having trophic function; -​ promotes growth and maturation of the reproductive system during puberty to make it active). Then it has other reproduction-related effects (develops sex drive; -​ controls gonadotropin hormone secretion through feedback). -​ It has effects on secondary sexual characteristics (causes voice to deepen because vocal fold thicken; induces male patter of hair growth; promotes muscld growth responsible for the male body configuration) -​ it has some non-reproductive actions (protein anabolic effect; promotes bone growth and then closes epiphyseal plates after being converted to estrogen by aromatase depending on the amount of hormone can lead to growth but during adulthood the amount of the sex hormone will close the epiphyseal plate. In this system time matters a lot and according to the moment the same hormone can lead to either growth or stop of growth). Androgens have anabolic effect. In the table it is shown that testosterone induces to aggressive behavior, however this happens in case of excess. This is something which allows for example to protect the female, in animal world, and hence it is a pro-active behavior in order to establish a hierarchy for instance Spermatogenesis Spermatogenesis is a very effective production. There is a lot of gametes available, and they are not only abundant but even mobile. The cells in charge of this process are the germ cells and Sertoli cells. ​ (this part is skipped as we did it already). It takes 64 days to pass from spermatogonia to mature sperm and up to several hundred million sperm are produced daily. The three stages are -​ the mitotic proliferation, -​ meiosis -​ packing. First there are primary spermatocytes, then secondary and then spermatids which will undergo packing. Packing is the remodeling of the haploid cells as at the end of packing there is the production of specialized and mobile spermatozoa from spermatids and the only the essential is kept. A mature spermatozoa has three parts: ​ The head consists primarily of the nucleus, which contains the Sperm’s complement of genetic information. ​ The acrosome, an enzyme-filled vesicle that caps the tip of the head, is used as an “enzymatic drill” for penetrating the ovum. The acrosomal enzymes remain inactive until the sperm contacts an egg, at which time the enzymes are released. They are used to overcome the barrier of the oocyte to enter it. The oocyte become permissive only to the first spermatozoa. ​ Tail, movement of which is powered by energy generated by the mitochondria concentrated within the midpiece of the sperm The seminiferous tubules house the Sertoli cells, which are epithelial cells, in addition to the developing sperm cells. The spermatozoa from precursor to mature sperm develop being engulfed by the Sertoli cells which protect the developing sperms. The Sertoli cells form a ring around the tubule lumen, with each Sertoli cell spanning the entire distance from the outer surface of the seminiferous tubule to the fluid-filled lumen. The cytoplasm of the Sertoli cells envelops the migrating sperm cells. Function of Sertoli cells: ​ They also separate the place where sperm production occurs and the blood. Therefore, the Sertoli cells form a blood–testes barrier. ​ The “nurse” Sertoli cells provide nourishment for developing sperm cells. ​ The Sertoli cells have an important phagocytic function. They engulf the cytoplasm extruded from the spermatids during their remodeling, and destroy defective germ cells ​ The Sertoli cells secrete into the lumen seminiferous tubule fluid, which “flushes” the released sperm from the tubule into the epididymis for storage and further processing. ​ An important component of this Sertoli secretion is androgen- binding protein (ABP) binding androgens (testosterone), maintaining a very high level of this hormone within the seminiferous tubule lumen. ​ The Sertoli cells are the site of action for control of spermatogenesis by both testosterone and follicle-stimulating hormone (FSH). The Sertoli cells themselves release another hormone, inhibin, which acts in negative-feedback fashion to regulate FSH secretion at the level of the axis Inhibin, together with testosterone, acts at the level of the axis with a negative feedback. In the axis gonadotropin releasing hormone-FSH/LH-gonads. GnRH is asking to produce both LH and FSH. In males, differently from female LH and FSH have different targets and functions. LH targets Leydig cells and receptors for LH are located on these cells asking for testosterone production, then testosterone reaches seminiferous tubules where it binds to ABP (released by Sertoli cells) and some testosterone will instead go into bloodstream to exert the other functions. FSH has its receptor on Sertoli cells, which will enhance all their functions related to sperm production. At the same time, they also produce ABP to keep testosterone in site. Sertoli cells will also produce inhibin acting on the axis. Having only testosterone as feedback would mean that the brain would only have half of the story, instead if the brain reaches also inhibin it means that also Sertoli cells are working in the proper way The seminal vesicles empty in the last portion of the ductus deferens on each side and supply fructose to nourish the ejaculated sperm, as once out it cannot be nourished anymore. This allows the sperm to survive enough to reach the target site, energy is needed for motion of the tail. These vesicles also release prostaglandins which stimulate motility of the sperm, they provide bulk of semen and provide the precursor for the clotting of the semen. Clotting is needed after the deposition (and not before) in order to keep the semen inside once the penis is withdrawn. Prostate gland secretes alkaline fluid that neutralizes the acidic vaginal secretion. Alkaline factors also trigger the semen clotting to keep the sperm in the vagina. Semen is not only spermatozoa, but also nourishment, prostaglandins, clotting factors, alkaline factors. Bulbourethral gland secretes mucus for lubrication. These accessory glands are not accessory as they are essential for deposition for correct fertilization. 6.​ Female reproductive system The production of sperm is continuous in male adult life, whereas in female the release of ova is intermittent. This behavior is explained by the fact that secretion of female sex hormones has a precise time course which has a cyclic temporal profile that occurs monthly. Every month in the adult female there is the availability of the gamete, which means the possibility to be fertilized. There is a precise window of time in which this can occur. Given that the fertilization is coupled with pregnancy, the female system does not only cyclically provide the gamete, but even the conditions for the housing of the embryo. Therefore, every month the female reproductive system prepares for a possible pregnancy. The whole reproductive system in female is hence influence by the monthly variations. During each cycle the female reproductive tract is prepared for implantation. If fertilization does not occur the cycle repeats. If fertilization occurs the other cycles are interrupted while the female system switches into the pregnancy modality. At the beginning, there is the corpus luteum will keep up the system until the development of the placenta which will take over the endocrine function of the corpus luteum. Oogenesis is a complex process which starts very early in prenatal life and then stops to then start again before puberty and then there is the cyclic phase which is the one following puberty. What is important to understand is where the ovarian cycle has to be placed in the timeline. There are 4 steps in oogenesis. -​ The step 1 is in fetal life, -​ the step 2 is in the pre-pubertal life -​ step 3+4 are in post-puberty period. The process allowing the egg to be ovulated starts three months before the ovulation. Step 1: fetal life The undifferentiated primordial germ cells in the fetal ovaries, the oogonia divide mitotically primary oocites. (6 - 7 million oogonia by the fifth month of gestation, when mitotic proliferation ceases). Step 2: Pre-pubertal life In this step occurs the formation of primary oocytes and primary follicles. Primary oocytes: (diploid) remain in this state of meiotic arrest for years until they are prepared for ovulation (only after puberty). They are basically frozen at the first stage of meiotic division and hence are diploid. Before birth, each primary oocyte is surrounded by a single layer of connective tissue which will become granulosa cells. Oocyte + surrounding granulosa cells = primary follicle capable of producing a single ovum. After the formation of the follicle, some oocytes are lost and these are the ones not surrounded by granulosa cells. Oocytes that are not incorporated into follicles: apoptosis (cell suicide). At birth, 2 million primary follicles remain, no new oocytes or follicles after birth. It is necessary to distinguish what happens to the cell in terms of meiotic division and what happens to the cell in terms of follicle formation. These structures will be sensitive to hormones only when hormones are released with certain time course. It is not enough to have estrogens, but it is necessary to acquire the correct timeline. The axis has to work with a precise time course and this only occurs at puberty, the hormone per se is not enough to force reproduction as for reproduction the axis has acquire a specific pulsativity which is acquired only at puberty. The primary follicle, during puberty will start to go towards maturation, becoming secondary follicle and acquiring the final feature which will force the maturation of the oocyte. Once started the cycle, each cycle will bring a group of primary follicle into the process of maturation until when one oocyte, out of the group, will be ovulated whereas the rest of the oocyte will be discharged. Until puberty it is possible that some follicles start to develop due to paracrine action of other hormones produced by granulosa cells, but these will die as they are not yet controlled by the correct amount of hormone with correct time course. Out of 2 millions follicle, this process mentioned above of development before the right time (before puberty) will lead to only 300.000 remaining follicles. Out of 300.000 only 400 will mature and be released. Clearly this is a selective process and the female needs to be careful as she does not have the same chance as males to carry on the genetic material. Considering the pre-pubertal life (and also prenatal) at 5-6 weeks there is the cortical migration of oogonia and the start of proliferation. In week 9-13 some oogonia start 1 meiotic division. New cells are called primary oocytes. This process completes within the 6° month fetal life (pre-natal). One layer of granulosa cells surrounds primary oocytes (oocyte -granulosa-basement membrane), now becoming primordial follicles. 20°-30° week: Start evolution of primordial follicles into primary follicles (enlargement of the oocytes and appearance of the zona Pellucida). This process ends within 6 months post-natal life. Step 3: post-puberty From puberty to menopause every month there will be a group of primary follicles trying to conclude the maturation. The mechanism determining which follicles within the pool will develop during a given cycle are unknown. Further development of a follicle is characterized by growth of the primary oocyte and by expansion and differentiation of the surrounding cell layers. The follicle becomes complex, there are granulosa cells (which become more trophic), theca cells (surrounding granulosa ones), the development of the antrum and so on. The fluid inside is important as it will increase the hydrostatic pressure needed to push the oocyte out, hence ovulation is a mechanical event. Before ovulation, the primary oocyte (the nucleus has been in meiotic arrest for years), completes its first meiotic division. This division yields two daughter cells (each receiving a haploid set of 23 doubled chromosomes). Almost all the cytoplasm remains with one of the daughter cells, now called the secondary oocyte, which is destined to become the ovum. The chromosomes of the other daughter cell, together with a small share of cytoplasm, form the first polar body. In this way, the ovum-to-be loses half of its chromosomes to form a haploid gamete but retains all of its nutrient- rich cytoplasm. The nutrient-poor polar body soon degenerates. From puberty to menarca, there is the process of maturation with the formation of the secondary follicle characterized by the basement membrane, zona pellucida and theca cells surrounding granulosa; in the tertiary follicle there is the antrum development and the hyperplasia of the thecal layer; then in the graafian follicle which is the one ovulating is characterized by the cumulus oophorus keeping the ovum in the center of the fluid. Step 4: post-puberty The secondary oocyte is the one ovulated and NOT the mature ovum. The final step of the production of the haploid cell occurs only if the oocyte is fertilized and not before. It is the sperm that fosters the second step of meiotic division. When the sperm fertilizes the division is completed and during this division, a half set of chromosomes, along with a thin layer of cytoplasm, is extruded as the second polar body. The other half set of 23 unpaired chromosomes remains behind in what is now the mature ovum. It is only when the 23 maternal chromosomes fuse with the 23 paternal one that the fertilization is complete. Example: generally it is thought that the December cycle, for instance, is characterized by a group of follicles entering cycle and among them one will be ovulated. However, this is not what happens, as those follicles entering step 3 and step 4 of maturation are selected in October (3 months before, with the third being the good one), but who is deciding which are the follicles that will develop during a given cycle as this process is gonadotropin independent? This is unknown. In the image above, there is the first and second cycles which are the one selecting the pool of follicles to be developed. In the enlargement, it is shown the late luteal phase of the second cycle and the beginning of the third cycle (early follicular) and what can be noticed is that there will be a dominant oocyte being selected and then in the late follicular phase, just before ovulation, there is one winning and the other follicles will be discharged. Nobody knows who is choosing the pool of follicles, but something about why one is dominant might be due to the fact that it is the one expressing more receptors for FSH. 7.​ Ovarian cycle The ovarian cycle consists of alternating follicular and luteal phases. In the follicular phase the dominant hormone is the estrogen, while in the luteal phase the dominant hormone is progesterone (but still estrogen is present). If fertilization occurs, the corpus luteum will become the corpus luteum of pregnancy and this structure will sustain the endocrine production during the first stage of pregnancy until placenta will take over this role. The ovary has two related endocrine units: (1)​ the estrogen-secreting follicle during the first half of the cycle (2)​ the corpus luteum, which secretes both progesterone and estrogen, during the last half of the cycle. The estradiol derives from testosterone without it no estrogen can be produced. The estradiol and estrone are the most important estrogens released -​ by 95% from ovaries and -​ 5% by peripheral conversion. Progesterone is released -​ for 50% by adrenal cortex (this layer of the adrenal also produces androgens apart form progesterone) -​ the other 50% by corpus luteum. The collaboration between theca cells and granulosa cell is important. The theca cells produce androgens and it is only in the granulosa cells that have aromatase able to convert testosterone into estradiol. To convert androgen into estrogen, aromatase is needed. Theca cells have receptors for LH and produce androstenedione which reaches by paracrine action the granulosa cells which have aromatase that will produce estradiol that then enters the follicular fluid or circulation. Theca cells have many receptors for LH, while granulosa cells express receptor for FSH. Even estrogen has a binding protein as for testosterone. These are the variations of the blood concentration of estradiol and progesterone. In the follicular phase estradiol is low and then increases until ovulatory phase to then decrease again in luteal phase. Estrogens are always there, and estrogen are a lot during ovulation. Progesterone is very low in follicular phase and becomes dominant in luteal phase. The effects of female sex hormones is the same as in males and there are also post-natal functions and non-reproductive effects (secondary sexual characteristics and growth function). This image shows all the axis (both male and female), in male there is testosterone and in females estrogen and progesterone. In females there is follicular phase where FSH is dominating and the luteal phase where LH is dominant. Given that there is only one gonadotropin releasing hormone, how comes that the hypophysis understands that i the first 14 days more FSH has to be produced and in the second 14 days more LH has to be produced? In males is easier as they both go parallelly, but in female the 2 hormones are not produced in a parallel way. What decides is pulsativity, when there is higher frequency of pulses the hypophyses releases it is time for FSH, when pulses decreases LH is release. 3 pulses per hour lead to FSH secretion, and 1 pulse per hour lead to LH secretion. This is how the hypophysis understands which hormone has to be released, in males the pulsativity is present but it is fixed and does not change. Endocrinal control of Ovarian cycle: There are 2 phases of the cycle with negative feedback and one phase of the cycle with positive feedback. Early follicular Considering the first day of the cycle as the first day of menstrual flow, in the early follicular phase there is dominance of FSH and slight increase of LH. There is maturation of follicle, the theca cells produce androgens and the granulosa cells transform androgens in estrogens. Granulosa cells are very sensitive to FSH (up- regulation receptors). The negative feedback of FSH on the axis stops the new follicles. Later follicular Then in the late follicular phase there is estrogen peak, the granulosa cells start expressing LH receptors (LH receptors expression hence move from theca cells to granulosa cells) getting ready for luteal phase. Progesterone starts being produced by granulosa cells. When there is the cocktail of estrogen peak + progesterone in small amount, this will exert positive feedback on the axis enhancing the peak of both FSH and LH. However, the peak of LH is larger. The peak of LH is due to positive feedback on the axis thanks to the cocktail of progesterone and estrogen. There is both a peak of FSH and LH (green portion of the right graph), but it is called peak of LH as it is larger. Why don’t there is not a peak of FSH as well? This is because inhibin produced by granulosa cells will go on hypophysis and decrease FSH production. Hypothalamus pushes for both, but then inhibin will limit FSH production. LH surge is the phase forcing ovulation. This LH surge brings about four major changes in the follicle: 1.​ It halts estrogen synthesis by the follicular cells 2.​ It reinitiates meiosis in the mature follicle’s oocyte, which had been in meiotic arrest since fetal development. 3.​ It triggers production of local prostaglandins, which induce ovulation by promoting vascular changes that cause rapid follicular swelling, enzymatic digestion of the follicular wall leading to rupture of the weakened wall of the bulging follicle 4.​ It causes differentiation of follicular cells into luteal cells. It terminates the follicular phase and initiates the luteal phase Both granulosa and theca cells will form the corpus luteum. The fallopian tubes are equipped with fimbriae that will capture the egg. Luteal phase In the luteal phase there is a progesterone peak, there is a start of estrogens increase (but are less than pre-ovulation). Then there is the corpus luteum formation and the decrease of FSH and LH secretion due to the negative feedback exerted by high amount of estrogen and progesterone. The key is progesterone as the follicle always produces estrogens. What changes is the time course and amount of estrogens, the appearance of progesterone of small amount (LH surge) and then the increase of progesterone that in high amount blocks the axis. The inhibin is only a modulator and when there is the change from FSH to LH is not due to inhibin (which does not act on the hypothalamus but on hypophysis). There are parallel actions of estrogens and progesterone on the endometrium and the reproductive system. There is also a uterine cycle that in the follicular phase undergoes proliferative phase and during luteal phase the endometrium undergoes secretory phase. The secretory phase leads to a thickening of the endometrium, which is very high with glands and vessels. If fertilization does not occur, trophic factors drop and glands and vessels are constricted at the very origin and everything is discharged with the menstrual flow.  8.​ Puberty In strict sense, the term puberty refers to the period of the life of an individual during which he/she undergoes the body modifications characteristic of sexual maturation, and the child becomes an adult with reproductive ability. Principal events: ​ Adrenergic steroids production (adrenarca) ​ Maturation of gonadic function ​ Acceleration of growth (pubertal growth spurt) ​ Fusion of epiphyseal plates (stop elongation) The important question is, who is the hormone acting at the level of the system and at the level of GH secretion to promote the final phase of bone elongation. Both androgens and estrogens are produced in the gonads, so who are the one pushing the last phase? It seems that are the estrogens, even if it was thought to be the androgens. This is because female with gonadic agenesia do not show pubertal spurt and administration of estrogens at low doses (< than those needed for the mammary gland development) recovers growth. Males and females lacking p450 aromatase do not show the spurt, no matter if androgens are normal or increased. Therefore, estrogens are the one more likely to be involved. When both hormones are very high in blood for a long time, there will be closure of epiphyseal plates. 9.​ Male and female sexual maturation In prepuberty, there are androgens. What is interesting is that at the very beginning of our life we seem adults as pulsativity is present and hormone concentration is like in adults, but then pulsativity is stopped (reduced amplitudes of pulses and decrease in gonadotropin) to be regained at puberty. The baby at 6 months in both male and female has pulsativity. At puberty, the androgens adrenal gland are the one forcing the expression of both axillary and pubic hairs. Then pulsativity is acquired again and starts the physiological reproductive ability. Pulsativity is relevant as it allows to not have constant amount of sex hormones in blood. In males the reproductive ability never ends. The cessation of a woman’s menstrual cycles at menopause sometime between the ages of 45 and 55 has traditionally been attributed to the limited supply of ovarian follicles present at birth. According to this proposal, once this reservoir is depleted, ovarian cycles, and hence menstrual cycles, cease. Menopause is preceded by a period of progressive ovarian failure characterized by increasingly irregular cycles and dwindling estrogen levels. Bringing about many physical and emotional changes. Males do not experience complete gonadal failure as females: (1)​ a male’s germ cell supply is unlimited because mitotic activity of the spermatogonia continues. (2)​ gonadal hormone secretion in males is not inextricably dependent on gametogenesis, as it is in females