Lecture Notes: Reproductive Biology PDF

MBBS (Hons Physiology), M.Sc. (Physiology), PhD (Physiology), MD, FWACS (OBGYN), FMCOG, FICS, FAcadMedS, FNAMed, MPA, cert ART, cert Cosmetic GYN]. 1 LECTURE NOTES, REPRODUCTIVE BIOLOGY Uchenna Nwagha Introduction The reproductive system consists of males and fem...

MBBS (Hons Physiology), M.Sc. (Physiology), PhD (Physiology), MD, FWACS (OBGYN), FMCOG, FICS, FAcadMedS, FNAMed, MPA, cert ART, cert Cosmetic GYN]. 1 LECTURE NOTES, REPRODUCTIVE BIOLOGY Uchenna Nwagha Introduction The reproductive system consists of males and females. The male gonad is called the testis, while the female gonad is called the ovary. These are responsible for the differences between the two systems. The differentiation of the primitive gonad into the testis or the ovary is genetically determined. After birth, the gonads remain quiescent until adolescent, when they are activated. The testis produces spermatozoa and male sex hormones while the ovary produces ova and female sex hormones. With advancing age, ovarian follicles regress, and reproduction seizes. However, there is a slow decline in gonadal function in the male, but the ability to produce spermatozoa persists and may never stop completely. Genetic and chromosomal sex differentiation The human body has two major types of cells, somatic (body cells) and highly specialised germ cells. The somatic cells have two copies of each chromosome arranged in pairs, one from each parent (diploid number of chromosome), containing 46 chromosomes. Forty-four (44) chromosomes are called; autosomes and are arranged in homologous pairs numbered (1-22). The remaining pair is the sex chromosome. In the female, it is called XX, while in the male, it is called the XY chromosome. The germ cells are in the testis and ovaries only. They contain one copy of each chromosome (haploid number). The male germ cell has either a 23X or a 23Y number of chromosomes, while the female germ cells always contain a 23X chromosome so that at fertilisation, diploidy is reestablished. The XY chromosomes determine maleness. Situated on the short arm of the Y chromosome is a region called the sex-determining region of Y chromosomes (SRY gene). This gene encodes the testis determining factor and is closely related to a glycoprotein H-Y antigen. The H-Y antigen is responsible for the differentiation of indifferent gonads to the testis. Furthermore, the hormonal effect on both the external and internal genitalia is determined by the X chromosome component, which contains the gene for the androgen receptor. Thus, the ability to produce a male child depends solely on the genetic composition of the germ cell selected from the male, as the female will always contribute to the X chromosome. After meiotic division, the female produces one germ cell (ova,23x) while the male produces four germ cells (spermatozoa, 2 (23X) and 2 (23Y). The female state is neuter as the development of the ovary becomes automatic in the absence of the Y chromosome; however, a normal X chromosome is vital for the further development of the female genitalia. In the female somatic cells, only one x chromosome is active. The other condenses and forms a bar body near the nuclear membrane. It can also form a nuclear drumstick in 1-15% of PMNL. Human chromosomes can be studied in detail by growing them in tissue culture, arresting mitosis at metaphase using colchicine, staining with nuclear dyes and examination under the microscope. The somatic cells multiply by mitosis while the germs cells multiply by meiosis.  Mother Father 2 46(XY) Parent 46(XX) Spermatozoa Ova 23(X) 23(Y) 23(X) 23(X) 46(XX) 46(XX) 46(XY) 46(XY) Girl Girl Boy Boy EMBRYOLOGY OF THE REPRODUCTIVE SYSTEM The gonads of both sexes are identical up till the 6th week of intrauterine life. They develop from the genital ridge, a condensation of tissue on the posterior abdominal wall. By the 3rd week of intrauterine life, primitive germ cells migrate from the yolk sac to the genital ridge, developing cortex and medulla. If the fetal chromosome is 46 xx, the medulla regresses, and the cortex develops into ovaries. If it was 46 XY, the cortex regresses, and the medulla develops into the testes. Despite the gonadal differentiation at 6 weeks, the genitalia (both external and internal) are still in their primordial form. Their differentiation begins from the 8th week, and between 10-12 weeks, one can identify separate genitalia. In the absence of a functional testis, the Mullerian ducts will develop into the tubes, uterus, and part of the vagina. In the presence of functional testis, the Sertoli cells produce Mullerian inhibiting substances that stimulate the degeneration of the Mullerian duct and develop the Wolffian duct to male internal genitalia. Sex and Gender Sex relates specifically to the biological, physical characteristics which make a person male or female gender is the system of classification based on sex. Individuals have usually formed the habit of interchanging it with the word sex. However, gender refers to the behaviours associated with members of that sex. Because of this apparent overlap in word usage, it is crucial to use the terms male and female while talking about sex and masculine and feminine while describing gender. Sex is more constant, but gender roles vary from culture to culture. Thus, many are complex, contentious, and less absolute. Classification of Sex Sex can be classified into seven categories: (i) Genetic sex: In the male, the SRY gene is active while inactive in the female. (ii) Chromosomal sex: In this group, the male contains the Y chromosome while the female provides the X chromosome. (iii) Gonadal sex: In this situation, the male has testis while the female has ovaries. (iv) Gametic sex: Here, spermatozoa are present in the male while the ova are present in the female.  3 (v) Hormonal sex: The male contains androgens and Mullerian inhibiting substances while these are absent in the female, which, in addition, has “female sex hormones.” (vi) External phenotypic sex: The male possesses a penis and scrotum while the females have a clitoris and labia. (vii) Internal phenotypic sex: The males have vas, prostate, and seminal vesicles while females have an oviduct, uterus, and vagina. (viii) Sex of rearing: This is determined by a combination of factors and depends mainly on the direction of the phenotypic sex irrespective of the other components. It can be determined early in childhood by parents who decide for the child and later by the subject who feels they were wrongly assigned. Abnormal sexual development (a) Chromosomal abnormalities This can be due to nondisjunction (a part of a chromosome fails to separate), translocation or deletion. Examples include, (i) Klinefelter’s Syndrome – 47xxy (read up on the characteristics) (ii) Turner’s syndrome – 45xo (iii)Super females – 47 xxx (iv) 45yo (is incompatible with life) (b) Hormonal abnormalities (i) True hermaphrodites – Individuals have both ovaries and testis and produce male and female hormones in almost equal amounts. (Check 582 textbook endo) (ii) Female pseudohermaphrodites – Have xx genetic composition and the ovary, but exposure to male sex hormones at 8th-13th weeks gestation leads to virilisation of external genitalia. (iii)Male pseudohermaphrodites – The individuals have XY genetic composition and a testis. However, malfunction of the testes leads to the nonproduction of Mullerian inhibiting substances and testosterone. Abnormal male genitalia or female internal and external genitalia thus develop. PUBERTY, CLIMACTERIC AND MENOPAUSE Puberty. Puberty is defined as a period when endocrine and gametogenic functions of the gonads have developed to a point where reproduction is possible. By the 4th week of intrauterine life, GnRH secretion begins, which culminates in the appearance of FSH and LH by 10-12 weeks, with the peak occurring at mid-gestation. However, in utero, fetal FSH level is suppressed due to a high oestrogen environment. Immediately after birth, FSH activity rises due to the removal of the foetus from the high estrogen environment. This rise persists for 6-18 months and then remains quiescent. FSH pulses are almost undetectable during childhood, but at 8-9 years, the pulses start gradually and then rise in amplitude and duration. Furthermore, as pulse frequency increases, the ratio of plasma LH to FSH rises with nocturnal peaks of LH at early and mid-puberty. Factors that initiate these hormonal changes at puberty are unclear but may be associated with increased fat and bone mass, as evidenced by increased leptin levels. It tends to occur earlier in moderately obese girls and later than average in severely underweight and malnourished, thus indicating that critical body weight may be necessary. Significant influences like GABA and kisspeptin have also been implicated. Pubertal age in girls is 8-13 years and in boys 9-14 years. There is, however, a slight delay in our environment due to our socioeconomic  4 and environmental conditions. Other situations that lead to delay include race, climate, and familial. Subjects with some genetic disorders, e.g., sickle cell disease, usually have delayed puberty. As our socioeconomic conditions begin to improve, it is expected that the age at menarche might approach that of Caucasians. In girls, the first event is breast development (the thelarche) and the growth spurt, followed by the development of hairs (adrenarche) on the pubic (pubarche) and axillary region induced by DHEA and DHEAS, and then menstruation (menarche). The average age for menarche in the developed world is 12.6 years and occurs 2 years later in our environment. There is also associated psychosocial development like shyness; heterosexual inclinations crave freedom and independence. The first physical sign in boys is an enlargement of the testis. Then an increase in the size of the penis, and scrotum. Sperm production begins at about 13yrs of age. There is also muscular growth and bone growth. The growth spurt in puberty occurs two years earlier in girls than in boys. This leads to earlier epiphyseal closure in girls, thus making boys taller, generally. Removal of the testis (castration) before puberty leads to delayed epiphyseal closure and continuous growth in bone length (a technique employed in animals to enhance growth). Other signs of puberty in boys included thickness of skin, formation of acne, male-type hair distribution (hairs on the face, chest, legs, etc.), baldness and deepening of the voice. Oestrogen-induced breast enlargement may occur in some individuals, but this usually recedes as testosterone production predominates. Adolescent period. The period of puberty and further maturation to adulthood (10-19 years) is called the adolescent period. This adolescent period is crucial in the life of every individual. There is a high incidence of drug abuse, cultism, armed robbery, sexual abuse and perversion, unwanted pregnancy, and sexually transmitted diseases, including HIV and AIDS. This underscores the need to handle this period with utmost care in other to avoid these vices. Precocious puberty is said to occur when secondary sexual characteristic occurs before 7-9 yrs. (see Ezeilo for causes of precocious puberty) and delayed puberty occurs when secondary sexual characteristics in males and menarche in females occur after 20 yrs. and 17 years, respectively. Menopause. The last menstrual period.it is a diagnosis in retrospect made after waiting for one year without a period. In females, it is marked by permanent cessation of menstruation. It occurs between 45-55 years. Although the testis function tends to decline slowly with advancing age, there is no male menopause like that of the female. With advancing age, the ovarian follicles begin to atrophy. Ovarian hormones (oestradiol) also continue to decline to deficient levels. This leads to loss of feedback inhibition on the hypothalamus and pituitary, with the eventual gross elevation of gonadotropins. The predominant oestrogen is oestrone, a product of the ovary's adrenal and stromal cells via peripheral aromatisation of androgens. (Note the terms pre- menopause, perimenopause, and post menopause The term climacteric is the period of the waning of ovarian function, which includes menopause. After menopause, then comes the postmenopausal period. Various changes occur because of hormonal alteration at menopause. (a) Menstruation becomes irregular and heavy initially and then eventually stops (menopause). (b) Psychological changes, e.g., depression, insomnia, irritability, nervousness, and headaches, occur. (c) Vasomotor changes other things that can happen include hot flushes, d. physical changes due to collagen loss. genital atrophy (causing dyspareunia), osteoporosis (fracture)  5 e. Metabolic changes increased incidence of coronary artery disease and. These symptoms can be reversed by hormone replacement therapy with oestrogen and progestogens. Premature menopause occurs when menstruation stops before 40 years of age. (Explain in detail each of the points) PHYSIOLOGY OF HUMAN SEXUAL RESPONSE In the initial phase of their studies, from 1957 until 1965, they recorded some of the first laboratory data on the anatomy and physiology of human sexual response based on direct observation of 382 women and 312 men in what they conservatively estimated to be "10,000 complete cycles of sexual response." They jointly wrote two classic texts in the field, Human Sexual Response and Human Sexual Inadequacy, published in 1966 and 1970. Both books were best sellers and were translated into more than thirty languages. Initially, due to the discrete nature of this topic, it was difficult to research human sexual responses. However, physiologists and physicians are now accepting sexual function as a legitimate area of interest and study. Masters and Johnson enumerated four stages of sexual response: excitement, plateau, orgasm, and resolution. Excitement. The excitement phase (also known as the arousal phase or initial excitement phase) is the first stage of the human sexual response cycle. It occurs due to any erotic physical or mental stimulation such as kissing, petting, or viewing erotic images, which leads to sexual excitement. Identifying the erogenous zones enhances excitability During the excitement stage, the body prepares for sexual intercourse In males, this involves penile erection. Receptors located on the glans penis are the most important. They are aided by receptors on other parts of the genitalia. Psychic impulses, e.g., thinking erotic thoughts, and seeing a naked woman, also play a vital role. With the stimulation of these receptors, impulses are carried to the brain for integration. Efferent parasympathetic impulses are sent back to the penis to cause vasodilatation and dilatation of the smooth muscles of the corpora spongiosa and cavenosa. This leads to increased blood flow into the sinuses, engorgement, and erection. The nerve endings also elaborate vasoactive intestinal peptides and nitric oxide (NO). Some of the nervi erigenti contain nitric oxide synthase. No activates guanyl cyclase to form cGMP. CGMP is a potent vasodilator, and its action leads to engorgement and erection. Sildenafil (Viagra) is a powerful aphrodisiac act by preventing the inactivation of CGMP. It inhibits the phosphodiesterase enzyme. The scrotum becomes tense, and the testicles are drawn up to the perineum. Female excitement involves enlargement of the breast, nipples, areola, clitoris, and proximal vagina and Vaso congestion of the skin (sex flush occurs). There is also associated mucus secretion from the Bartholin's gland and venous plexus in the vagina. Plateau: In males, this is the interval between erection and ejaculation. The size of the organs continues to increase. There is associated emission from the testicles, epididymis, vas deferens prostate, seminal vesicles urethral and bulbourethral glands, and may contain spermatozoa. Urethral sphincter contracts to prevent retrograde ejaculation. In females, engorgement and lubrication continue to the extent that interoital opening is reduced by 50% to enable a firm grip of the penis (orgasmic platform). Both men and women may begin to vocalise involuntarily Orgasm: This is the height of sexual tension and synchronises with emission and ejaculation in the male. Each ejection is associated with a wave of sexual pleasure and  6 euphoria. The penis, loin, lower spine, and lower back are usually involved. The first and second convulsions are often the most intense in sensation and produce the highest quantity of semen. After that, each contraction is associated with a diminishing volume of semen and a milder wave of pleasure. Sympathetic stimulation of the vas, prostate and seminal vesicles leads to the emission of semen into the internal urethra. Contraction of the cavernous muscles aided by muscles of the pelvic floor and body trunk leads to ejaculation of the sperm to the exterior. There are associated hyperventilation, tachycardia and hypertension and other effects of sympathetic discharge. Females have a pleasurable contraction of pelvic organs and musculature; unlike males, females can experience multiple orgasms in one sexual act. It is accompanied by quick cycles of muscle contraction in the lower pelvic muscles, which surround both the anus and the primary sexual organs. Women also experience uterine and vaginal contractions. Orgasms are often associated with other involuntary actions, including vocalisations, muscular spasms in other body areas, and a generally euphoric sensation. Note the terms vaginal and clitoral orgasm Resolution: This is the interval between ejaculation and returns to the standard physiological baseline. The refractory period is the interval between ejaculation and the next possible excitement. It is variable and depends on the age and psychological state of the patient. It occurs mainly in males (it may not be so in a few men). It may be as long as a few minutes to several (hours). Is not prominent in females. That is why females have multiple orgasms. Elderly The first scientists to research the sexual responsiveness of older adults were masters and Johnson. It was discovered that sexual ability does not disappear with age in the presence of good health and the availability of an interested and attractive partner. However, it takes older men longer to become aroused, and the amount of vaginal lubrication tends to diminish with age. Clinical Correlates 1. The inability to achieve an adequate and robust erection is called impotence. Impotence can be mild, moderate, or severe. Most of the time, aetiology is psychological, but sometimes medical conditions have been implicated. The inability of the penis to relax after an erection is called priapism. Medical conditions have been involved, e.g., sickle cell disease. Premature ejaculation occurs before or just after penetration. 2. Female frigidity 3. Vaginismus (This is the result of a reflex contraction of the pubococcygeus muscle, Homosexuality and lesbianism 4. Hypoactive sexual desire disorder (HSDD) is considered a sexual dysfunction, and HSDD is characterised as a lack or absence of sexual fantasies and desire for sexual activity for some period. To be considered a disorder, it must cause marked distress or interpersonal problems and not be better accounted for by another mental disorder (i.e., depression), a drug (legal or illegal), or some other medical condition.  7 Two types exist Impotence The inability to achieve an adequate and robust erection is called impotence. Impotence can be mild, moderate, or severe. Most of the time, aetiology is psychological, but sometimes medical conditions have been implicated. The inability of the penis to relax after an erection is called priapism. Medical conditions have been implicated, e.g., sickle cell disease. Premature ejaculation occurs before or just after penetration. Hypoactive female sexual dysfunction disorder. Here the following parameters are assessed and scored Desire, Arousal, Lubrication, Orgasm, Satisfaction and Pain. Female frigidity is an extreme example of hyposexuality Female hypersexuality /Nymphomania Vaginismus (This is the result of a reflex contraction of the pubococcygeus muscle, Sexual pervasion, Homosexuality, and lesbianism Reproductive Health: According to WHO, reproductive health is a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity in all matters relating to the reproductive system, its functions, and processes. These include health education, childbearing, family planning, prevention of STDs and safe sex. The peculiar biological nature of women makes them vulnerable, with a high burden of ill health in matters relating to the reproductive system. Thus, the urgent need to protect the reproductive rights of women should therefore not be overemphasised. These rights include the following. ❖ To decide who, when, and where to marry and the number of children to have. ❖ Decide her well-being throughout life in all matters of reproductive health. ❖ Have a responsible, healthy, and satisfying sex life. ❖ Unrestricted access to information on reproductive health to make an informed decision ❖ A cheap, available, safe, and effective method of family planning. ❖ Safe pregnancy and delivery. ❖ Free from sexual assault/violence  8 ❖ Privacy in matters relating to reproductive health. Men also have reproductive health problems, but the amplitude is not the same as that of women. THE MALE REPRODUCTION SYSTEM Functional Anatomy The testes are the primary sex organs that correspond to the ovary in the female. The outer layer of the testes is called tunica albuginea, which radiates into the testis dividing it into many pyramidal lobules with the bases directed towards the periphery. Each lobule contains coiled tubes called seminiferous tubules, 30-70 cm long and 150- 300μm in diameter. Each testis contains about 900 seminiferous tubules, consisting of three layers, the outermost connective tissue, basement membrane and a complex stratified epithelium (germinal epithelium). Functional anatomy of the testis The complex stratified epithelium contains two types of cells, 4 to 8 layers of sperm- forming cells at various degrees of maturation and single sustentacular cells of Sertoli, which extend from the basement membrane to the lumen, providing support for the sperm-forming cells. At the periphery of the basement membrane lie the interstitial cells of Leydig. The Sertoli cells are joined to one another at about the mid-portion of their lateral walls by tight junctions. The seminiferous tubules converge towards the apex of the lobules to form straight tubules, which pass into the mediastinum testes to join a network of rete testes. From the rete testes, efferens ductuli emerge to form the head of the epididymis, which continues to the body, and tail and finally creates the vas deferens. The vas is joined by the ducts of the prostate and seminal vesicle to form the ejaculatory duct, emptying into the prostatic urethra.  9 Structure of the seminiferous tubules Accessory sex organs Including the prostate, seminal vesicles, urethra, and penis. These organs produce their secretions which add to that of the testis to form semen. The penis is used in the physical process of sexual intercourse. Spermatogenesis Spermatogenesis is the process of developing spermatozoa from a primitive germ cell, and it is inhibited in the fetus by the meiosis-inhibiting factor. It begins at puberty and continues throughout life, although it decreases markedly during old age. About 100-200 million spermatozoa can be produced daily. It occurs in the seminiferous tubules and can be divided into three phases. Mitosis: The primordial germ cells divide mitotically to produce spermatogonia (A or B) next to the seminiferous tubule's basal lamina. The A cell group is like the original cell and acts as a reservoir for spermatogonia. The B group undergoes further mitotic division leading to primary spermatocytes; a process also called spermatocytogenesis. Meiosis: Each primary spermatocyte undergoes the first meiotic division (after pairing homologous chromosomes and exchanging chromatid segments) to produce two diploid secondary spermatocytes. Each diploid (23 double-stranded) secondary spermatocytes further divide meiotically to create two haploid spermatids. Thus, each primary spermatocyte provides four spermatids. Several primary spermatocytes are produced from one primitive germ cell. It is therefore estimated that one spermatogonium gives rise to 64 spermatids.  10 Spermiogenesis; The spermatids now get embedded into the substance of the Sertoli cells for differentiation to mature spermatozoa. This involves nuclear condensation, shrinkage of cytoplasm, and development of the head, acrosome, middle piece, and tail. Thus, one primary spermatocyte gives rise to 4 haploid mature spermatozoa. The mature spermatozoa now enter the lumen of the seminiferous tubules from where they are propelled to the vas. Spermatogenesis takes approximately 60-70 days to accomplish. Sertoli cells; Are large pyramidal-shaped cells that can withstand adverse temperature, ionising radiation, chemical assault, malnutrition, and infections. Their functions include Endocrine functions: The Sertoli cells produce Mullerian inhibitory factor (MIF), inhibin and oestrogen. Exocrine functions; Secretes seminal fluids rich in K+, HCO3- but low in Na+ and Cl-. Synthesises androgen binding protein and the histocompatibility antigen Y (H-Y antigen). Maintenance of spermatids; Provides mechanical support and nutrition for the sperm. Phagocytosis of a cytoplasmic fragment detached from transforming spermatozoa and aids in the release of sperm. Blood testis barrier: The tight junction of the Sertoli cells prevent harmful chemicals in the blood from getting to the lumen of the tubules to cause damage. This barrier also prevents the entry of mature sperms into the bloodstream to induce an immune reaction, and it ensures a high local concentration of testosterone. Factors that affect spermatogenesis. 1. Hormonal factors: Early in spermatogenesis, FSH stimulates Sertoli cells to function maximally. LH stimulates the Leydig cells to produce testosterone (which controls later) and epidermal growth factor. Hormones of the Sertoli cells include oestradiol, stromal growth factor, insulin-like growth factor, inhibin and activin. These target hormones (testosterone inclusive) interact actively in an autocrine and paracrine manner among Leydig, peritubular, Sertoli, and germ cells to modify sperm production. GH stimulates while oestrogens negatively inhibit GnRH and the conversion of testosterone to DHT. Androgen binding protein, another product of Sertoli cell, binds avidly to testosterone oestradiol  11 and DHT, a situation of extreme value in concentrating these products in the testis for all essential autocrine, paracrine action. 2. Body temperature: The scrotal temperature is 2C below body temp. Any condition that encourages high temperature, e.g., Constant wearing of tight nylon pants, long distant lorry drivers, and cryptorchidism, leads to reduced spermatogenesis. Spermatozoa can survive for years at extremely low temperatures. In the presence of glycerol, it can be stored at -269oc and revived after storage by thawing. This is the basis for the formation of a sperm bank during artificial reproductive techniques. 3. Congenital absence of the testis or inflammation of the testis (orchitis) reduces spermatogenesis. Sperm maturation and Transport The sperm takes several days to pass through the epididymis. The pressure of Sertoli fluids, peristaltic movements, and ciliary actions of ductular cells aid this movement. Sperm is stored in the epididymis and vas for at least a month, and during this period, it acquires motility characteristics but no full potential for fertilisation. The spermatozoa's ability to fertilise the ovum is further enhanced when deposited in the female genital tract. It develops total motility and swims up at 3mm/min, reaching the tubes within 30-60 minutes. Here two processes occur. They are capacitation and acrosomal reaction. Capacitation. This is not well understood, but it is believed that the uterine and fallopian fluids wash away the various inhibitory factors that can suppress sperm activity. Acrosomal reaction; Hyaluronidase and proteolytic enzymes necessary for penetration of corona radiata and zona pellucida are released during this process. STRUCTURE OF MATURE SPERMATOZOA Acrosome Mitochondria 5 μm 50 μm 5 μm 5 μm End Piece Principal Piece Middle Piece Head Semen The head has excellent penetrating power; the middle piece has abundant energy storage while the tail maintains propelling ability of the spermatozoa. Semen. The semen is the product of ejaculation during male sexual acts. It consists of spermatozoa (10%), secretions from the seminal vesicle (60%), and secretion from the prostate (30%). Secretions from the bulbourethral and urethral glands constitute