Reproductive Anatomy and Physiology BIOM1052 PDF

Reproductive Anatomy and Physiology BIOM1052 A/Prof Josephine Bowles [email protected] @JosBowles Learning objectives: Gain a solid understanding of the scientific principles that govern reproduction in mammals, especiall...

Reproductive Anatomy and Physiology BIOM1052 A/Prof Josephine Bowles [email protected] @JosBowles Learning objectives: Gain a solid understanding of the scientific principles that govern reproduction in mammals, especially humans Background for future para-medical careers Useful to know as an educated member of society Understand concepts more than just memorise facts Appreciate that reproductive systems have an impact on many other aspects of health Relax, learn and enjoy – the subject of reproductive biology concerns every one in this class. It is one of the most interesting, most fun, and least boring topics in life! The only system that is not essential for the survival of an individual The only system that is essential for the survival of the species The reproductive system has only two functions 1. Gametogenic function – Support germ cells – the cells that ultimately become sperm and eggs 2. Endocrine function – Secrete hormones (development and function of reproductive organs, secondary sex chracteristics, pregnancy, childbirth, lactation) - Essentially ensures that sperm and eggs can do their job  * = 37.2 trillion cells 1 sperm cell 1 oocyte cell “Your somatic cells are your own Your germ cells belong to the species” *generic male, not actual partner Topics we will cover: 1. Sex determination (how do we become male or female?) 2. Gametogenesis and meiosis (how do we make haploid germ cells?) 3. Male reproductive anatomy, physiology and spermatogenesis (how do male humans ensure that they are able to reproduce?) 4. Female reproductive anatomy, physiology and oogenesis (how do female humans ensure that they are able to reproduce?) 5. Fertilization, implantation and pregnancy 6. Contraception 7. Assisted reproductive technologies (ART) 8. Endocrine disrupting chemicals 1. Sex determination How is sex determined in most mammals? Genetic sex XX or XY chromosomal constitution (determined at conception) Gonadal sex Bipotential gonad develops into either testis or ovary (determined during fetal life) Phenotypic sex Determined by hormonal secretions of the gonad (begins before birth and continues throughout life) In mammals, female development is default Default = the program that will run unless something intervenes Males and females both develop the same type of gonad initially ‘indifferent’ or ‘bipotential’ gonad Y chromosome has the SRY gene If SRY protein is produced at the right time, then it triggers a cascade of gene expression that leads to the formation of a testis rather than an ovary SRY is the male sex-determining gene – the gene on the Y that makes an embryo become male 1. Mutated in XY female humans 2. Ectopic expression in XX mouse embryos 14 kb fragment of Y chromosome containing Sry gene Causes XX embryo to develop as male! Injecting DNA into a one cell mouse embryo SRY is the male-determining gene on the Y chromosome 6 weeks in humans SRY makes the ‘indifferent gonad’ develop into a testis rather than an ovary  The mammalian fetus has the potential to develop as either male or female AMH = anti-Mullerian hormone AMH causes the Mullerian duct to degenerate AMH Testosterone causes the Woliffian duct to remain INSL3 necessary for testis descent Kobayashi and Behringer, 2003 AMH So what’s the difference between sex and gender? ‘Man’ and ‘woman’ are also gender descriptors Gender is a social construct. woman/girl man/boy non-binary Gender reveal party?? transgender Sex reveal party genderqueer agender Sex is based on biology and is usually assigned at birth. female male intersex or DSD (disorders of sex development – i.e. sex is not binary!) Gender is a social construct. woman/girl man/boy non-binary transgender genderqueer agender Sex is based on biology and is usually assigned at birth. female male intersex or DSD (disorders of sex development – i.e. sex is not binary!) (< 0.02%) 2. Gametogenesis and meiosis Gametes = fancy word for sperm and eggs. Specialised sex cell carrying 23 chromosomes (somatic cells carry 46 chromosomes) What is the point of gametogenesis (making gametes)??? In order to have sexual reproduction, two haploid gametes (ovum and sperm) must combine to make a diploid zygote which will grow into a new individual Q. How do we make haploid cells? A. Meiosis!  Gametogenesis -1 Gametogenesis - the process whereby diploid precursor cells undergo meiotic division to become haploid gametes (sperm/spermatozoa and eggs/ova) The precursor cells are called germ cells and they are already present during fetal life (they are very vulnerable during this time – more about that later!) To produce eggs and sperm both mitosis (cell division) and meiosis (reductive cell division) are required  Gametogenesis -2 The testis produces spermatozoa (sperm) almost without limit Sperm are small, mobile, plentiful and easy to make During adult life, men produce about 290 million sperm cells per day (1500 per second) The ovary produces a limited number of ova (singular = ovum; mature eggs) during life. The number of oocytes (immature eggs) is fixed before birth; this is the ‘ovarian reserve’ Ova are large, take lots of energy to make, are not very mobile After puberty, once a month, one oocyte will finish development and be released (then called ovum because mature) Both sperm and eggs are haploid (one copy of each chromosome) When a sperm and ovum combine, they produce a single diploid cell (‘zygote’) that contains all instructions necessary to make a new organism  *Only one pair of the 23 pairs in Duplicate each humans is chromosome 2n shown – two chromatids What is meiosis? Reductive division of a diploid nucleus to form haploid nuclei Diploid = two copies of every chromosome (one from mum, one from dad), 2n Haploid = one copy of every chromosome, 1n 1n So ‘reductive’ means go from 2n to 1n 1n  Paternal Maternal homologue homologue *Only one What happens during meiosis? pair of the 2n Synapsis and crossing over occur between 23 pairs in humans is homologous chromosomes – this is the shown opportunity to achieve recombination. Because of recombination, genes from the paternal and maternal chromosomes are mixed Meiosis I – separation of homologous chromosomes (reduction – 2n to 1n) 1n Meiosis II – separation of sister chromatids Result - 4 haploid cells (and genetically all 1n are different)  Germ cells Spermatogenesis birth Before birth, germ cells are already present in the testis (Stem cell) After birth, germ cells migrate to the periphery of the seminiferous tubules and become spermatogonia (germline stem cells; singular is spermatogonium) Primary spermatocyte Testosterone When the stem cell divides, one of the offspring differentiates into a primary spermatocyte while the other replaces the stem cell Meiosis is triggered by increase in testosterone at puberty First meiotic division produces 2 secondary spermatocytes Second meiotic division produces 4 haploid spermatids The spermatids go through a process of differentiation (condense nucleus, grow a tail) to become spermatozoa (sperm) So from one primary spermatocyte males make 4 haploid sperm  Oogenesis Oogenesis begins during fetal life but then arrests in prophase of the first meiotic division (prophase I) (plural oogonia) Retinoic acid (RA) triggers the onset of meiosis in all oogonia RA and onset of meiosis A newborn girl has all the eggs she will ever have (all in prophase of meiosis I). This is called the ‘ovarian reserve’. There are no ‘stem cells’. LH (for some) At puberty, every month LH (from the anterior pituitary) triggers several primary oocytes to finish the first meiotic division (arrested) Division of primary oocytes is unequal with one set of chromosomes and most of cytoplasm and organelles going to one cell (secondary oocyte), the rest to polar body. The secondary oocyte arrests (metaphase of meiosis II) If a secondary oocyte is fertilized it completes meiosis II and a fertilized egg is produced (half chromosomes from ovum, half from sperm) From one primary oocyte, only one ovum is produced (other nuclei are in polar bodies and these degenerate) Spermatogenesis compared with oogenesis Begins at puberty Begins during fetal life Depends on stem cells so unlimited Number of oocytes determined by supply of sperm throughout life birth (‘ovarian reserve’) Release of sperm from testis Release of 1 or very few oocytes continuous (about 1500 every occurs monthly second) Oocyte is largest cell in human Sperm tiny (10,000 times smaller body (approx. 0.12 mm) than oocyte) 3. Male reproductive anatomy, physiology and spermatogenesis What is the aim? Testes produce both sperm and androgens such as testosterone The vas deferens allows the sperm to transfer to the outside of the body through the penis. Gland secretion makes up most of the volume of the semen The sperm are made within the seminiferous tubules Vas deferens 800 metres of seminiferous tubules  Spermatogenesis Process of spermatozoa (sperm) formation Begins at the outermost layer of cells in the seminiferous tubules and proceeds toward the lumen At each step of the process the daughter cells move closer to the lumen In cross section, see tubules at different stages of development (Sertoli cell) (includes Leydig cells that produce Testosterone) (Stem cells) The different stages of sperm cells are embedded within Sertoli (nurse) cell cytoplasm (Sertoli cells) (make hormones) (stem cells)  The final sperm have no organelles other than the acrosome -reduce the cell’s size and mass The sperm is Acrosome – organelle that forms during spermiogenesis essentially just a It contains enzymes that help the sperm penetrate the coating of the egg carrier of the chromsomes  Flagella are very similar to cilia, seen in other biological systems Sperm are highly differentiated cells Defects in flagella directly affect sperm motility, Differential interference contrast microscopic image and often lead to failure of fertilization  Sertoli (nurse) cells Maintain the blood-testis barrier (isolates the seminiferous tubules from the general circulation – ‘privledged’*). Physically surround all stages of the germ line and support their development Because transport across the Sertoli cells is very regulated the conditions in the luminal compartment remain very stable. *analogous to the ‘blood-brain barrier’  Sertoli cells Receive instructions. FSH* (from the anterior pituitary) and testosterone (from the Leydig cells) act on Sertoli cells Support mitosis and meiosis. In response to the FSH and testosterone signals, Sertoli cells stimulate mitosis of spermatogonia and meiosis of spermatocytes Support spermiogenesis. Nurse cells surround and enfold the spermatids, providing nutrients and chemical stimuli. Secrete Inhibin (in response to factors released by developing sperm). Inhibin feeds back to depress production of FSH by the anterior pituitary Secrete Anti-Mullerian Hormone. This function occurs during fetal life - AMH causes regression of the Mullerian ducts (these form the uterine tubes and uterus in females) *FSH = follicle stimulating hormone (we will talk about this later) Leydig cells ‘Interstitial’ cells – reside in the tissue between the seminiferous tubules Produce testosterone (starts around the 7th week of pregnancy) Prenatal testosterone triggers development of the Wolffian duct so that male sexual organs form (epididymus, vas deferens, seminal vesicle) Prenatal testosterone also affects the CNS especially the developing hypothalamus (so that at puberty it will respond appropriately – i.e. this part of the brain is masculinized prior to birth) Leydig cells also produce testosterone at puberty and throughout life Testosterone levels high in the testis (maintain spermatogenesis) but testosterone also released into the systemic circulation (muscle development, bone growth, male secondary sexual characteristics, libido)  Puberty D e c li ne w Masculinise the embryo ith a ge Mini-puberty Testosterone also produced by females, though the levels are lower than in males Male hormones - 1 In human males, puberty starts at about 11 or 12 years of age Onset of puberty is largely influenced by hormonal activity The hypothalamus begins secreting frequent high level pulses of GnRN (gonadotropin-releasing hormone) GnRH acts on the anterior pituitary causing it to release follicle stimulating hormone (FSH) and lutenizing hormone (LH) for the first time FSH enters the testes, stimulating the Sertoli cells which then trigger the onset of spermatogenesis LH enter the testes, stimulating the Leydig cells (interstitial cells) to make and release testosterone into the testes and the blood Male hormones -2 In addition to triggering spermatogenesis, testosterone is the hormone responsible for secondary sexual characteristics (deepening of the voice, growth of facial, axillary and pubic hair) Feedback -When the sperm count gets high, Sertoli cells produce and release Inhibin into the blood stream; Inhibin feeds back to the anterior pituitary to stop producing FSH -Testosterone feeds back through the blood stream to the hypothalamus and anterior pituitary to inhibit release of GnRH, FSH and LH  Hormones control sperm production in a negative feedback system The ‘HPG axis’ (hypothalamus-pituitary-gonad) H P G FSH (Follicle Stimulating Hormone) Q – Some men use anabolic steroids (synthetic – induce spermatogenesis at puberty testosterone) to bulk up their muscles. LH (Luteinising Hormone) Given what you understand about hormonal control in – induce production of testosterone at puberty males, what do you think the risk might be? Further maturation of sperm occurs in the male reproductive tract One little appreciated feature of the male reproductive system is that, when spermatids leave the testis, they are not capable of fertilizing an oocyte The male reproductive tract matures, nourishes, stores and transports sperm Efferent Ducts Epididymis Vas deferens Urethra The Male Reproductive Tract Sperm detach from the Sertoli cells inton the lumen of the seminiferous tubule. They look like mature sperm, but functionally they are not – they are immobile. The sperm pass out of the testis via the rete testis into the efferent ducts. Fluid currents, created by cilia lining the efferent ducts, transport the immobile sperm into the epididymis. The epididymis is about 7 metres long and is highly coiled with head (caput), body (corpus) and tail (cauda) sections. Sperm are stored primarily in the cauda. to vas deferens The tail of the epididymis attaches to the vas deferens. The epididymis is responsible for the storage and maturation of sperm 1. Sperm transport. Total transit time is 10 – 15 days. Transport is achieved by rhythmic peristaltic contraction of smooth muscle layers, especially strong at the cauda 2. Sperm concentration. More than 90% of the luminal fluid that leaves rete testis is absorbed by epithelial cells of the epididymis. Stereocilia increase the surface area available for this function. High sperm concentration is important for male fertility. 3. Sperm storage. Sperm are stored in the cauda epididymis prior to ejaculation. Vas deferens Long muscular tube that connects the epididymis to the urethra Begins at the tail of the epididymis and ascends through the inguinal canal. It passes posteriorly in the abdominal cavity, curving along the surface of the bladder and toward the prostate gland. 40 – 45 cm long Transports mature sperm to the urethra before ejaculation Peristaltic contractions propel sperm and fluid along the duct. Sperm can be stored (for up to several months) The accessory glands Seminiferous tubules and epididymis produce only about 5% of volume of the semen The other 95% is a mixture of secretions from three glands: Seminal glands Prostate gland Bulbourethral glands  A pair of glands - located on posterior side of Seminal glands the bladder Each about 15 cm long Very active secretory glands, providing about 60% of the volume of the semen Main component of section - fructose – used by mitochondrial of sperm to fuel their movement through the female reproductive tract When sperm come into contact with secretions of seminal glands, particularly fructose, they begin beating their flagella (now they are motile!) Prostate gland About 4cm in diameter Encircles the urethra as it leaves the urinary bladder Produces about 20 – 30% of the volume of semen Prostatic fluid produced contains seminalplasmin, a protein with antibiotic properties that may help prevent urinary tract infections in males Also contains a compound that coagulates the sperm (temporary thickening of semen to help retain it in the female reproductive tract) Bulbourethral glands Paired glands at base of the penis Round and only about 1cm in diameter Secrete thick alkaline mucous to neutralize any urinary acid that may remain in the urethra What could possibly go wrong? Male infertility Infertile because sperm are not produced (‘non-obstructive azoospermia’) Infertile because sperm cannot exit the body (‘obstructive azoospermia’) Infertile or subfertile because defects in flagella affect sperm motility Benign Prostatic hypertrophy Enlargement of the prostate gland (typically occurs spontaneously in men over 50 years old, because interstitial cells of testis producing less testosterone) The swelling constricts and blocks the urethra, and can cause kidney damage Prostate cancer Second most common cancer, and rates increasing for unknown reasons What could possibly go wrong? Cystic Fibrosis (CF) Genetic condition (mutations in the CF gene) – predominantly a lung disorder, but various problems all due to abnormal buildup of mucus Around 97 % of men with CF are infertile because sperm cannot exit the body (‘congenital bilateral absence of the vas deferens’) - the problem originates during fetal development because mucus buildup prevents proper formation of the duct. So would this be considered ‘obstructive azoospermia’ or ‘non-obstructive azoospermia’?. Because sperm never make it to the semen – semen is thinner and lower in volume Vas deferens missing, but sperm are not (so the men are infertile, but they are not sterile) Most men with CF can still have biological children through assisted reproductive technology (ART) – but because the sperm have not travelled along the reproductive ducts they are not mature enough to fertilize without help (need to use a procedure called ICSI – see ART later in the lecture)  What could possibly go wrong? 5a-reductase type 2 deficiency (one example of ‘Intersex’) (LGBTIQ) 46,XY genotype Problems arise in the male sexual differentiation stage Autosomal recessive (so consanguinity is risk factor) Testosterone is produced but it is not converted to DHT because 5a-reductase type 2 does not function Testis forms, Mullerian structures lost and Wolffian duct differentiates so internal genitalia is typical of a male (and testes can make sperm) At birth - external genitalia is typical for a female – testes have not descended and remain internal, penis does not develop because this requires DHT At puberty, testosterone causes development of secondary male sex characteristics (deepening voice, muscle mass development). Another enzyme (5a-RD type 1) is produced at puberty, and this can cause some virilisation of the external genitalia. Athlete Caster Semenya (XY athlete assigned ‘female’ at birth)  What could possibly go wrong? Testicular Dysgenesis Syndrome Group of conditions that are increasing in prevalence especially in developed countries (includes male infertility, testicular cancer, low testosterone levels, intersex) ‘Endocrine disrupting’ chemicals Kilcoyne and Mitchell, Arch Dis Child, 2017 Features of Testicular Dysgenesis Syndrome Cryptorchidism - testes fail to descend into the scrotum (7th month of pregnancy) – very common (e.g. about 4% of newborn boys) but usually fixes itself within months. More likely to develop testicular cancer. Hyperspadias – malformed penis (the opening not at the tip) Testis germ cell cancer – the most common cancer in young males – germ cells in the fetal testis do not develop properly and reactivate at puberty to form tumors Primary hypogonadism – low serum testosterone levels and high FSH and LH levels Low sperm count – spermatogenesis not well supported References Fundamentals of Anatomy and Physiology. (Martini et al, PEARSON) http://www.abc.net.au/news/2017-10- 14/reduced-fertility-rates-common- chemicals-food-cleaning- products/9050212