Reproduction & Development Keypoints: Human Chromosomes Gametogenesis Fertilization Fetal development Maintenance of pregnancy Parturition

Terminology Gonads (testes and ovaries) External genitalia Produce gametes(spermatozoa and ova) Gametes are from germ cells External genitalia Internal genitalia Autosomes vs. sex chromosomes Meiosis

Human Chromosomes and Sex Determination How many autosomes? Sex chromosomes? X-linked disorders, Examples Barr body = “extra” X-chromosome in female Nondisjunction during meiosis Barr Body

SRY (or TDF) The Sex-Determining Region (SRY) is a gene that encodes a transcription factor that is a member of the high mobility group HMG-box family of DNA binding proteins. The gene is located on the short arm of the Y chromosome and has a gene map locus - Yp11.3.Common synonyms of the gene name are Testis Determining Factor (TDF) and Testis Determining Factor on Y (TDY).   The Y chromosome currently has 77 genes mapped in its cytogenetic map (OMIM). The SRY protein is Y-linked and encoded at its map locus of Yp11.3 in between the genes for RPS4Y: ribosomal protein S4 and another protein product sequence that has an unknown function.   The main function of the SRY protein is to initiate male sex determination as a transcriptional activator, which regulates a genetic switch in male development.  The SRY HMG box recognizes DNA by partial intercalation in the minor groove.  The SRY protein then binds to the DNA and distorts its shape (SRY protein in action).  In doing so, it regulates genes that control the development of the testes (NCBI). The SRY protein is somewhat of a special protein - it has only one exon.  Evidence for this finding has been studied and published in Genomics "Evidence that the SRY protein is encoded by a single exon on the human Y chromosome."  (Genomics 736-739).   Its coding sequence codes for 204 amino acids from a mRNA sequence that is 897 base pairs long- distributed in the following among the four nucleotides: Fig 26-2

Human Life Cycle Review meiosis Gametogenesis

most cases of human trisomy originate from errors in maternal meiosis I. Given the biology of the human egg, this is not entirely unexpected: the first stage of female meiosis is initiated in the fetal ovary and is followed by a long "arrest" phase that lasts until the time of ovulation. Thus, the first meiotic division is amazingly protracted, taking at least 10 to 15 years and as many as 45 to 50 years to complete.

Nondisjunction Men usually have only one X and one Y chromosome, i.e. the chromosome constitution 46,XY. Men with XYY syndrome have two Y chromosomes, and the chromosome constitution 47,XYY. The frequency is approximately 1 of 1000 men, i.e. in Denmark, with 5 millions inhabitant, there are 3000 boys and men with XYY syndrome. You cannot see on a newborn boy, that he has the XYY syndrome. Except for increased height there are no special physical stigmata in boys and men with XYY syndrome. Their average height is approximately 7 cms. above the expected height. Physical development is otherwise normal, sex-organs are normal. Boys with XYY syndrome often are more physically active than their brothers, and if this activity is canalized into play, sports or other physical activities with parent and other children, this fact is in no way negative. Boys with XYY syndrome have a tendency to a delayed mental maturation, and in connection with an increased tendency for learning-problems in school, this means a need for early and adequate stimulation. They are generally lethal except monosomy X (female with one X chromosome) and trisomy 21 (Down’s Syndrome).

Abnormality Karyotype Down Syndrome: Trisomy 21 Turner Syndrome: X Triple-X Syndrome: XXX Klinefelter Syndrome: XXY Jacob Syndrome: XYY even though only a small proportion of aneuploid fetuses survive to term (primarily those with trisomy 13, 18, or 21 and those with various sex-chromosome abnormalities), aneuploidy is still the leading genetic cause of mental impairment and developmental disabilities. Triple X syndrome, also called trisomy X or 47,XXX, is characterized by the presence of one extra X chromosome in each of a female's cells. Most often, this chromosomal change causes no unusual physical features or medical problems. Females with triple X syndrome are sometimes taller than average and have an increased risk of learning disabilities and delayed speech and language skills. These characteristics vary widely among affected girls and women, however. Most females with triple X syndrome have normal sexual development and are able to conceive children. How common is triple X syndrome? This condition occurs in about 1 in 1,000 newborn girls. Five to 10 girls with triple X syndrome are born in the United States each day. XYY - Jacob Syndrome XYY males are tall, have acne, speech, and reading problems. Although there are a disproportionate number in penal institutions, 96% of Jacob's Syndrome men are normal. In the early 1970’s screening began in hospitals in England, Canada, Denmark and US. Families with XYY boys were offered "anticipatory guidance". These types of programs were stopped because they were self-fulfilling prophesies.

Turner Syndrome Monosomy X (45,X). Characteristically broad, "webbed" neck. Stature reduced, edema in ankles and wrists. Relatively normal lives – but no functional ovaries. 1 in 6,000 birth affected.

Klinefelter Syndrome XXY karyotype. Non-disjunction in meiosis (maternal or paternal)  ovum: XX; sperm: XY Usually normal – may be tall and have small testes. Infertility due to absent sperm. 1 in 1,500 males affected.

Nondisjunction of Autosomal Chromosomes TRISOMY 21: Most frequent viable autosomal aneuploidy.

Sex Determination Early gonad (< 6 weeks) is bipotential (indifferent gonad) SRY (Sex-determining Region of Y chromosome) gene on Y-chromosome codes for a protein that directs the gonad to become a testis If no SRY, gonad becomes ovary. Note that sex hormones are not yet produced! Testes produce Anti-Mullerian Hormone, Testosterone and DHT Development of male accessory organs Ovaries develop due to absence of SRY and AMH Estrogen directs development of female accessory organs

Intersex True hermaphrodite (both male and female gonads): relatively rare and poorly understood Pseudohermaphrodite – external genitalia of one sex and internal sex organs of the other sex. Mostly no ambiguity in the sex of the external genitalia  no question about gender at birth Male pseudohermaphroditism due to 5 α- reductase deficiency and  DHT production. Born with female external genitalia Androgen Insensitivity Syndrome = XY genotype, but no receptors for androgens. Thus, the phenotype is female. (not in book) At puberty,  testosterone causes development of male characteristics True hermaphroditism is rare but has been reported in more than 400 individuals.The diagnosis requires the presence of both ovarian and testicular tissue in either the same or opposite gonads.The external genitalia may simulate those of either a male or a female or may be ambiguous. Diagnosis and treatment at an early age is important . A person who has both testicular and ovarian tissue is said, in old terminology, to be a true hermaphrodite. Hermes was the God of Intelligence and Wisdom, and Aphrodite was the Goddess of Beauty and Love. A true hermaphrodite may have a separate ovary and testis but more commonly has an ovo-testis which is a gonad containing both sorts of tissue. This can be on one or both sides of the body. 60% of true hermaphrodites will have an XX karyotype and the remainder may have an XY karyotype or a mosaic (a mixture). The external genitalia may be ambiguous or female. There may be a uterus or (more commonly) a hemi-uterus (half uterus) on the side where there is ovarian tissue. The person may be raised female or male, and often undergoes genital surgery. The ovo-testis is usually removed because of the risk of malignancy. Pseudo-hermaphroditism is more common. From a medical standpoint, hermaphroditism suggests two factors: ambiguous external genitalia genitalia that do not match the genetic make-up of the person (example: female genitalia in a genetically male individual) The following conditions can produce ambiguous genitalia and hermaphroditism: congenital adrenal hyperplasia fetal exposure to sex hormones testicular feminization syndrome Symptoms    ambiguous genitalia at birth unusual appearing genitalia at birth hormone levels (for example, testosterone level) endoscopic examination (to verify the absence or presence of a vagina or cervix) ultrasound to evaluate whether internal sex organs are present (for example, a uterus) Treatment  The family of the infant needs to be informed of the child's condition as early as possible. It is a very sensitive time, requiring compassion and guidance to avoid feelings of guilt, shame, or discomfort. Early assignment of the sex is important for the emotional well being of the person. In large part, the decision is based on the corrective potential of the ambiguous genitalia, rather than on chromosomal determinants. The initial care should include a team of professionals that include neonatologists and pediatric specialists, endocrinologists, radiologists, urologists, psychologists, and geneticists.

Gametogenesis Starts in utero – resumes at puberty General principle same for males and females Male: continuous sperm manufacture. Meiosis produces 4 spermatozoa Female: born with all possible oocytes. Meiosis produces 1 ovum

Oogenesis: Egg Cell Formation Oogonia mitosis ceases before birth At birth: only primary oocytes – suspended in prophase of meiosis I (= prophase I)

Oogenesis after Birth: At puberty: ↑ estrogen initiates ovarian cycle ovulation 2nd meiotic division completed after fertilization

Male versus Female Gametogenesis Fig 24-5

Hormonal Control of Reproduction Directed by brain (hypothalamus, etc.) Both sexes produce androgens & estrogens (progesterone only in female) Main androgen = testosterone and DHT Main estrogen = estradiol Testicular and ovarian enzyme (aromatase) converts testosterone into estradiol Mechanism of action of steroid hormones?

Interactions Between Hypothalamus, Anterior Pituitary, and Gonads Short and long negative feedback loops as typical for homeostasis Special: High levels of estrogen  pos. feedback!  LH Peak

Biosynthetic Pathway for Steroid Hormones The flattened stroma cells forming a sheath or theca outside the basal lamina lining the mature OVARIAN FOLLICLE. Thecal interstitial or stromal cells are steroidogenic, and produce primarily ANDROGENS which serve as precusors of ESTROGENS in the GRANULOSA CELLS. Theca cells Synthesize androgens Granulosa cells convert androgens to estrogen diffusion

Female Reproduction Anatomy review: Ovaries and uterus

Menstrual Cycle lasts ~ 1 month range 24-35 days Ovarian cycle (changes in follicles) function: monthly production of gametes Uterine cycle (changes in endometrial lining) function: receive developing embryo

Ovarian Cycle Compare to Fig. 26-13 Luteal phase Follicular phase Ovulation estrogen progesterone

Uterine Cycle: regulated by hormones of ovarian cycle ? during luteal phase of ovaries Beginning of follicular phase of ovaries

Spermatogenesis Seminiferous tubules Sertoli cells: androgen binding protein blood testes barrier etc. Leydig cells testosterone vs. DHT