Pbl Exam 5 Case 4

Front 1

1. What are primordial germ cells?

Where do they come from and where do they migrate to?

Back 1

Gametes are derived from primordial germ cells that are formed in the epiblast during the second week and that move to the wall of the yolk sac.

During the fourth week, these cells begin to migrate from the yolk sac toward the developing gonads, where they arrive by the fifth week.

Front 2

2. What are teratomas?

What types of cells are responsible for them?

Back 2

Teratomas are tumors of disputed origin that often contain a variety of tissues, such as bone, hair, muscle, gut epithelia, and others.

It is thought that these tumors arise from a pluripotent stem cell that can differentiate into any of the three germ layers or their derivatives.

Some evidence suggests that primordial germ cells that have strayed from their normal paths could be responsible. Another source is epiblast cells migrating through the primitive streak during gastrulation.

Front 3

3. What is meiosis?

Back 3

Meiosis is the cell division that takes place in the germ cells to generate male and female gametes, sperm and egg cells, respectively.

Meiosis requires two cell divisions, meiosis I and II, to reproduce the number of chromosomes to the haploid number of 23.

As a result of meiosis, genetic variability is enhanced through crossover and through random distribution of homologous chromosomes to the daughter cells.

Front 4

4. What is synapsis?

Back 4

Homologous chromosomes align themselves in pairs, a process called synapsis.

The pairing is exact and point for point except for the XY combination.

Homologous pairs then separate into two daughter cells.

Front 5

5. What do homologous chromosomes consist of?

Back 5

Two chromatids

Front 6

6. What occurs during the crossover?

When does it occur?

Back 6

Crossovers occur during meisosis 1.

Crossovers are the interchange of chromatid segments between paired homologous chromosomes. Segments of chromatids break and are exchanged as homologous chromosomes separate. As separation occurs, points of interchange are temporarily united and form an X-like structure called a chiasma.

Front 7

7. What is a polar body?

Back 7

During meiosis, one primary oocyte gives rise to four daughter cells, each w/22 plus 1 X chromosomes.

However, only one of these develops into a mature gamete, the oocyte; the other three, the polar bodies, receive little cytoplasm and degenerate during subsequent development.

Front 8

8. What are the most common chromosomal abnormalities in abortuses?

Back 8

1. 45,X Turners
2. Triploidy
3. Trisomy 16

Front 9

9. What does diploid mean?

What does haploid mean?

Back 9

Normal somatic cells are diploid, or 2n

Normal gametes are haploid, or 1n

Front 10

10. What does euploid mean?

What does aneuploid mean?

Back 10

Euploid refers to any exact multiple of n, e.g. diploid or triploid.

Aneuploid refers to any chromosome number that is not euploid; it is usually applied when an extra chromosome is present (trisomy) or when one is missing (monosomy).

Front 11

11. What does nondisjunction mean?

When does it occur?

Back 11

In meiosis, two members of a pair of homologous chromosomes normally separate during the first meiotic division, so that each daughter cell receives one member of each pair.

Sometimes, however, separation does not occur (nondisjunction), and both members of a pair move into one cell. As a result, one cell receives 24 chromosomes and the other receives 22, instead of the normal 23.

When, at fertilization, a gamete having 23 chromosomes fuses w/a gamete having 24 or 22, the result is an individual with either 47 (trisomy) or 45 chromosomes (monosomy).

Nondisjunction occurs during either the first or second meiotic division of the germ cells and may involve the autosomes or sex chromosomes.

Front 12

12. What event produces mosaicism?

Back 12

Occasionally, nondisjunction occurs during mitosis (mitotic nondisjunction) in an embryonic cell during the earliest cell divisions.

Such conditions produce mosaicism, with some cells having an abnormal chromosome number and other being normal.

Affected individuals may exhibit few or many of the characteristics of a particular syndrome, depending on the number of cells involved and their distribution.

Front 13

13. What is an example of an unbalance translocation that produces Down syndrome?

Back 13

Unbalanced translocations between the long arms of chromosomes 14 and 21 during meiosis I or II produce gametes w/an extra copy of chromosome 21, one of the causes of Down syndrome.

Front 14

14. What are the three causes of Down syndrome?

Back 14

1. About 95% of cases of Down syndrome are caused by trisomy 21 resulting from meiotic nondisjunction, and in 75% of these instances, nondisjunction occurs during oocyte formation.

2. In approx 4% of cases there is an unbalanced translocation between chromosome 21 and 13, 14, or 15.

3. The final 1% is caused by mosaicism resulting from mitotic nondisjunction.

Front 15

15. What is trisomy 18?

Back 15

AKA Edwards syndrome

Features:
1. Mental retardation
2. Congenital heart defects
3. Low set ears
4. Flexion of fingers and hands
5. Micrognathia
6. Renal anomalies
7. Syndactyly
8. Malformations of the skeletal system

Incidence is 1/5,000 newborns; 85% are lost between 10 wks of gestation and term, whereas those born alive usually die by age 2 months.

Front 16

16. What is trisomy 13?

Back 16

AKA Patau syndrome

Features:
1. Mental retardation
2. Holoprosencephaly
3. Congenital heart defects
4. Deafness
5. Clef lip and palate
6. Eye defects, such as microphthamia, anophthalmia, and coloboma

The incidence is approx 1/20,000 live births, and over 90% of the infants die in the first month after birth.

Front 17

17. What is Klinefelter syndrome?

Back 17

Only found in males and the clinical features are usually detected at puberty. These are sterility, testicular atrophy, hyalinization of the seminiferous tubules, and usually gynecomastia.

The cells have 47 chromosomes with a sex chromosomal complements of the XXY types, and a sex chromatin body (Barr body) is found in 80% of cases.

Incidence is 1/500 males

Although mental retardation is not generally part of the syndrome, the more X chromosomes there are, the more likely there will be some degree of mental impairment.

Front 18

18. What causes Klinefelter syndrome?

Back 18

Nondisjunction of the XX homologues is the most common causative event.

Occasionally, patients with Klinefelter syndrome have 48 chromosomes: 44 autosomes and 4 sex chromosomes (XXXY).

Front 19

19. What is Turner syndrome?

Back 19

Turner syndrome, with a 45,X karyotypes, is the only monosomy compatible with life.

Even then, 98% of all fetuses w/the syndrome are spontaneously aborted.

The few that survive are female in appearance and are characterized by the absence of ovaries (gonadal dysgenesis), and short stature.

Other common abnormalities are webbed neck, lymphedema of the extremities, skeletal deformities, and a broad chest with widely spaced nipples.

Front 20

20. What causes Turner syndrome?

Back 20

Approx 55% of affected women are monosomic for the X and chromatin body negative b/c of nondisjunction.

In 80% of these women, nondisjunction in the male gamete is the cause.

In the remainder of women, structural abnormalities of the X chromosome or mitotic nondisjunction resulting in mosaicism are the cause.

Front 21

21. What is Triple X syndrome?

Back 21

Patients w/triple X syndrome are infantile, with scanty menses and some degree of mental retardation.

They have two sex chromatin bodies in their cells.

Front 22

22. What is a well known syndrome caused by a partial deletion of the short arm of chromosome 5?

What are the features of this syndrome?

Back 22

Cri-du-chat syndrome.

Such children have a cat-like cry, microcephaly, mental retardation, and congenital heart disease.

Front 23

23. What is an example of a syndrome caused by an inherited microdeletion?

Back 23

Angelman syndrome, if inherited the deletion on the maternal chromosome

Prader-Willi syndrome, if inherited on the paternal chromosome.

These are also examples of genomic imprinting

Front 24

24. What is Miller-Dieker syndrome?

What causes it?

Back 24

Other contiguous gene syndromes may be inherited from either parent, including Miller-Dieker syndrome.

Clinical features:
1. Lissencephaly (smooth brain)
2. Developmental delay
3. Seizures
4. Cardiac and facial abnormalities

Caused by a deletion at 17p13

Front 25

25. What is velocardiofacial (Shprintzen) syndrome?

What causes it?

Back 25

Clinical features:
1. Palatal defects
2. Conotruncal heart defects
3. Speech delay
4. Learning disorders
5. Schizophrenia-like disorder

Caused by a deletion at 22q11.

Front 26

26. What is fragile X syndrome?

What causes it?

Back 26

Fragile X syndrome is characterized by mental retardation, large ears, prominent jaw, and pale blue irises.

Males are affected more often than females. Fragile X is second only to Down syndrome as a cause of mental retardation b/c of chromosomal abnormalities.

It is caused by repeated fragile sites of CGG repeats on the long arm of the X chromosome (Xq27).

Front 27

27. What are oogonia?

Back 27

Once primordial germ cells have arrived in the gonad of a genetic female, they differentiate into oogonia.

These cells undergo a number of mitotic divisions, and by the end of the third month are arranged in clusters surrounded by a layer of flat epithelial cells.

Front 28

28. What are these flat epithelial cells called?

Back 28

These are known as follicular cells.

Whereas all of the oogonia in one cluster are probably derived from a single cell, the follicular cells originate from surface epithelium covering the ovary.

Front 29

29. What are primary oocytes?

Back 29

The majority of oogonia continue to divide by mitosis, but some of them arrest their cell division in prophase of meiosis I and form primary oocytes.

Front 30

30. What is a primordial follicle?

Back 30

All surviving oocytes past the seventh month have entered prophase of meiosis I, and most of them are individually surrounded by a layer of flat epithelial cells.

A primary oocyte, together w/its surrounding flat epithelial cells, is known as a primordial follicle.

Front 31

31. What is the diplotene stage?

What keeps the primary oocytes in this stage?

Back 31

Instead of proceeding into metaphase, they enter the diplotene stage, a resting stage during phophase that is characterized by a lacy network of chromatin.

Primary oocytes remain arrested in prophase and do not finish their first meiotic division before puberty is reached.

This arrested stage is produced by oocyte maturation inhibitor (OMI), a small peptide secreted by follicular cells.

Front 32

32. After puberty, each month 15-20 follicles begin to mature and pass through what three stages?

Which stage is the longest?

Back 32

1. Primary, or preantral
2. Secondary, or antral
3. Preovulatory (Graafian follicle)

The antral stage is the longest, whereas the preovulatory stage encompasses approx 37 before ovulation.

Front 33

33. What is a primary follicle?

Back 33

As the primary oocyte begins to grow, surrounding follicular cells change from flat to cuboidal and proliferate to produce a stratified epithelium of granulosa cells, and the unit is called a primary follicle.

Front 34

34. What is the theca folliculi?

Back 34

Granulosa cells rest on a basement membrane separating them from surrounding stromal cells that form the theca folliculi.

Front 35

35. What is the zona pellucida?

Back 35

Granulosa cells and the oocyte secrete a layer of glycoproteins on the surface of the oocyte, forming the zona pellucida.

Front 36

36. What is the theca externa and interna?

Back 36

As follicles continue to grow, cells of the theca folliculi organize into an inner layer of secretory cells, the theca interna, and an outer fibrous capsule, the theca externa.

Also, small, finger-like process of the follicular cells extend across the zona pellucida and interdigitate w/microvilli of the plasma membrane of the oocyte. These processes are important for transport of materials from follicular cells to the oocyte.

Front 37

37. What is a secondary follicle?

Back 37

As development continues, fluid filled spaces appear between granulosa cells. Coalescence of these spaces forms the antrum, and the follicle is called a secondary (vesicular) follicle.

At maturity, the secondary follicle may be 25 mm or more in diameter. It is surrounded by the theca interna, which is composed of cells having characteristics of steroid secretion, rich in blood vessels, and the theca externa, which gradually merges w/the ovarian stroma.

Front 38

38. What is the cumulus oophorus?

Back 38

Granulosa cells surrounding the oocyte remain intact and form the cumulus oophorus.

Front 39

39. What happens when the secondary follicle is mature?

Back 39

A surge in LH induces the preovulatory growth phase.

Meiosis I is completed, resulting in the formation of two daughter cells of unequal size, each with 23 double structured chromosomes.

One cells, the secondary oocyte, receives most of the cytoplasm; the other, the first polar body, receives practically none.

The cell then enters meiosis II but arrests in metaphase approx 3 hours before ovulation. Meiosis II is completed only if the oocyte is fertilized; otherwise, the cell degenerates approx 24 hours after ovulation.

Front 40

40. What are Sertoli cells, and why are they important?

Back 40

Sertoli cells are the supporting cells of the immature spermatocytes and are derived from the surface epithelium of the gland in the same manner as follicular cells.

Testosterone binds to Sertoli cells to promote spermatogenesis.

FSH also binds to Sertoli cells to stimulate testicular fluid production and synthesis of intracellular androgen receptor proteins.

Front 41

41. What do the male primordial germ cells give rise to?

Back 41

Spermatogonial stem cells.

At regular intervals, cells emerge from this stem cell population to form type A spermatogonia, and their production marks the initiation of spermatogenesis.

Type A cells undergo a limited number of mitotic division to form clone cells.

Front 42

42. What are type B spermatogonia, primary spermatocytes, and secondary spermatocytes?

Back 42

The last cell division from type A spermatogonia produces type B spermatogonia, which then divide to form primary spermatocytes.

Primary spermatocytes then enter a prolonged prophase followed by rapid completion of meiosis I and formation of secondary spermatocytes.

Front 43

43. What are spermatids?

Back 43

During the second meiotic division, these cells immediately begin to form haploid spermatids.

Front 44

44. What is spermiogenesis?

Back 44

The series of changes resulting in the transformation of spermatids into spermatozoa.

These changes include:
1. Formation of the acrosome
2. Condensation of the nucleus
3. Formation of neck, middle piece, and tail
4. Shedding of most of the cytoplasm

Front 45

45. What are the three major changes in the 1950's that improved our ability to observe chromosomes?

Back 45

1. Use of spindle poisons, such as colchicine and colcemid, that arrest dividing somatic cells in metaphase, when chromosomes are maximally condensed and easiest to see.

2. The use of a hypotonic (low salt) solution, which causes swelling of cells, rupture of the nucleus, and better separation of individual chromosomes.

3. The use of staining materials that are absorbed differentially by different parts of chromosomes, thus producing the characteristic bands that help to identify individual chromosomes.

Front 46

46. What are chromosome bands and how are they identified?

Back 46

Chromosome bands help to identify individual chromosomes and structural abnormalities in chromosomes.

Banding techniques include quinacrine, Giemsa, reverse C, and NOR banding.

High resolution banding, using prophase or prometaphase chromosomes, increases the number of observable bands

Front 47

47. What is FISH?

Back 47

Fluorescence in situ hybridization (FISH) is a technique in which a labeled probe is hybridized to metaphase, prophase, or interphase chromosomes.

FISH can be used to test for missing or additional chromosomal material as well as chromosome rearrangements.

Front 48

48. What is polyploidy?

Back 48

Polyploidy, the presence of a complete set of extra chromosomes in a cell, is seen commonly in plants and often improves their agricultural value.

Polyploidy also occurs in humans, although much less frequently. The polyploid conditions that have been observed in humans are triploidy (69 chromosomes in each cell nucleu).

Front 49

49. What is triploidy?

What is the most common cause?

Back 49

Triploidy is seen in only about 1/10,000 live births, but it accounts for an estimated 15% of the chromosome abnormalities occurring at conception.

The most common cause is the fertilization of an egg by two sperm (dispermy) The resulting zygote receives 23 chromosomes from the egg and 23 from each of the two sperm cells.

Front 50

50. What are two other causes of triploidy?

Back 50

It can also be caused by the fusion of an ovum and a polar body, each containing 23 chromosomes, and subsequent fertilization by a sperm cell.

Meiotic failure, in which a diploid sperm or egg cell is produced, can also produce a triploid zygote.

Front 51

51. What causes tetraploidy?

Back 51

Much rarer than triploidy.

Can be caused by a mitotic failure in the early embryo in which all of the duplicated chromosomes migrate to one of the two daughter cells.

It can also result from the fusion of two diploid zygotes.

Front 52

52. What does aneuploid mean?

What usually causes aneuploid conditions?

Back 52

Cells that do not contain a multiple of 23 chromosomes.

Aneuploid conditions consist primarily of monosomies and trisomies.

The most common cause of aneuploidy is nondisjunction, the failure of chromosomes to disjoin normally during meiosis.

Front 53

53. What medically significant problems occur w/increased freq among infants and children w/Down syndrome?

Back 53

1. Obstruction of the duodenum or atresia of the esophagus, duodenum, or anus
2. Respiratory infections
3. Increased risk (15-20x higher) of developing leukemia
4. Approx 40% are born w/structural heart defects
5. Conductive and sometimes neural hearing loss
6. Hypothyroidism
7. Various eye abnormalities

Front 54

54. What is the most common structural heart defect in children w/Down syndrome?

Back 54

The most common of these is an atrioventricular (AV) canal, a defect in which the interatrial and interventricular septa fail to fuse nromally during fetal development.

The result is blood flow from the left side of the heart to the right side and then to the pulmonary vasculature, producing pulmonary hypertension

VSDs are also common among babies w/Down syndrome.

Front 55

55. What is the most important single cause of decreased survival in those w/Down syndrome?

Back 55

Congenital heart defects.

Front 56

56. Who contributes the extra chromosome in Down syndrome - mother or father?

Back 56

In about 90-95% of cases the extra chromosome is contributed by the mother.

About 75% of these maternal nondisjunctions occur during meiosis I, w/the remainder during meiosis II.

Front 57

57. Describe mosiacism in Down syndrome

What is the most common cause?

Back 57

Mosiacism is seen in approx 2-4% of trisomy 21 live births.

These individuals have some normal somatic cells and some cells w/trisomy 21. This type of mosiacism in the male would be designated 47,XY,+21[10]/46,XY[10], with the numbers inside the brackets indicating the number of cells scored w/each karyotype.

The most common cause is a trisomic conception followed by loss of the extra chromosome in some cells during mitosis in the embryo.

Front 58

58. What gene is a candidate for mental retardation in Down syndrome?

Back 58

A candidate is DYRK, a kinase gene located on 21q.

Overexpression of this gene in the mouse causes learning and memory defects.

Another gene located in this critical region, APP, encodes the amyloid beta precursor protein.

A third copy of APP is likely to account for the occurrence of ALzheimer-like features in neraly all Down syndrome patients by 40 years of age. Mutations of APP cause a small percentage of Alzheimer disease cases, and children with partial trisomies that do not include the APP gene do not develop Alzheimer-like features.

Front 59

59. What medically significant problems occur w/increased freq among infants with trisomy 18?

Back 59

Most babies w/trisomy 18 have major malformations. Congenital ehart defects, particularly VSDs, are the most common. Other medically significant congenital malformations include omphalocele (protrusion of the bowel into the umbilical cord) diaphragmatic hernia, and, occasionally, spina bifida.

Front 60

60. 50% of infants w/trisomy 18 die within the first several weeks of life, and only about 5% are still alive at 12 months of age. What is the most common cause of death in trisomy 18?

Back 60

A combo of factors, including aspiration pneumonia, predisposition to infections and apnea, and congenital heart defects, accounts of the high mortality rate.

Front 61

61. What is trisomy 13?

Back 61

AKA Patau syndrome.

Clinical features consists primarily of oral-facial clefts, micropthalmia, and postaxial polydactyly. Malformations of the CNS are seen frequently,a s are heart defects and renal abnormalities.

Cutis aplasia may also be seen

Front 62

62. What is the genotypic presentation for trisomy 13?

Back 62

About 80% of patients with Patau syndrome have full trisomy 13.

Most of the remaining patients have trisomy of the long are of chromosome 13 due to a translocation.

It is estimated that 95% or more of trisomy 13 conceptions are spontaneously lost during pregnancy.

Front 63

64. What is the relationship between maternal age and trisomies?

Back 63

Nearly all autosomal trisomies increase w/maternal age as a result of nondisjunction in older mothers.

There is little evidence for a paternal age effect on nondisjunction in males.

Front 64

65. What is sex chromosome aneuploidy?

Back 64

Among live born infants, about 1/400 males and 1/650 females have some form of sex chromosome aneuploidy.

Primarily b/c of X inactivation, the consequences of this class of aneuploidy are less severe than those of autosomal aneuploidy.

With the exception of a complete absence of X chromosome material, all of the sex chromosome aneuploidies are compatible w/survival in at least some cases.

Front 65

66. What is Turner syndrome, and what causes it?

Back 65

Turn syndrome is most commonly caused by a 45,X karyotype.

Although this disorder is common at conception, it is relatively rare among live births, reflecting a very high rate of spontaneous abortion.

Mosiacism, including confined placental mosaicism, appears to increase the probability of survival to term.

Front 66

67. What are the chromosome abnormalities that cause Turner syndrome?

Back 66

About 50% have a 45,X karyotype in their peripheral lymphocytes.

At least 30-40% are mosaics, most commonly 45,X/46,XX and less commonly 45,X/46,XY.

Mosiacs who have Y chromosomes in some cells are predisposed to malignancies (gonadoblastomas) in their gonadal streaks.

About 10-20% of patients w/Turner syndrome have structural X chromosome abnormalities involving a deletion of some or all of the short arm.

Front 67

68. What causes 60-80% of monosomy X cases?

Back 67

Caused by the absence of a paternally derived sex chromosome, occurring either during early mitosis in the embryo or during meiosis in the father (i.e. the offspring receives an X chromosome only from the mother).

Front 68

69. What is confined placental mosaicism?

Back 68

Among those with Turner's that do survive to term, many are chromosomal mosaics, with mosaicism of the placenta alone (confined placental mosiacism) being especially common.

It is likely that the presence of some normal cells in mosaic fetuses enhances fetal survival.

Front 69

70. What specific genes are involved in the Turner syndrome phenotype?

Back 69

Mutations in the SHOX gene, which encodes a transcription factor expressed in embryonic limbs, produce short stature.

This gene is located on the distal tip of the X and Y short arms. Thus, it is normally transcribed in two copies in both males and females.

In females with Turners, this gene would be present in only one active copy, and the resulting haploinsufficiency is likely to contribute to short stature.

Front 70

71. What explains the reasoning behind why females w/Turners syndrome who receive the X chromosome from their father have higher verbal IQ scores and better social cognition?

Back 70

This difference implies the presence of a genomic imprinting effect on a specific region of the X chromosome.

Interestingly a study of partial deletions of the X chromosome showed that the imprinted region escapes X inactivation.

B/c normal females inherit active copies of this region from both parents, while males inherit a copy only from their mother, this finding could have important implications for general male-female differences in social cognition and verbal IQ.

Front 71

72. What is Klinefelter syndrome, and what is it caused by?

Back 71

Males with Klinefelter syndrome (47,XXY) are taller than average, may have a reduction in IQ, and are usually sterile. Testosterone therapy and mastectomy for gynocomastia are sometimes recommended.

The extra X chromosome is derived maternally in about 50% of Klinefelter cases, and the syndrome increases w/incidence with advanced maternal age.

Mosaicism, which is seen in about 15% of patients, increases the likelihood of viable sperm production.

Front 72

73. What is trisomy X, and what causes it?

Back 72

The 47,XXX karyotype occurs in approx 1/1,000 females and usually has benign consequences.

Overt physical abnormalities are rarely seen, but these females sometimes suffer from sterility, menstrual irregularity, or mild mental retardation.

Approx 90% of cases are the result of nondisjunction in the mother, and, as with other trisomies, the incidence increases among the offspring of older mothers.

Front 73

74. What is 47,XYY?

Back 73

Males w/this karyotype tend to be taller than average, and they have a 10-15 point reduction in average IQ.

There is evidence of minor behavioral disorder, such as hyperactivity, attention deficit disorder, and learning disabilities in males with this syndrome.

Front 74

75. What is the importance of the pseudoautosomal region of the Y chromosome?

Back 74

The distal portion of the Y chromosome is known as the pseudoautosomal region. Just centromeric of the pseudoautosomal region lies a gene known as the SRY gene.

This gene encodes a product that interacts w/other genes to initiate the development of the undifferentiated embryo into a male (including Sertoli cell differentiation, secretion of mullerian inhibiting substance, etc...)

Front 75

76. What is the SRY gene product a member of?

Back 75

The SRY gene product is a member of the high mobility group (HMG) family of DNA bending transcription factors.

By bending DNA, the protein is though to promote DNA-DNA interactions that rigger events in the developmental cascade leading to male differentiation.

In particular, SRY interacts antagonistically with DAX1, a gene that represses other genes that promote differentiation of the embryo into a male.

Front 76

77. What happens in the absence of SRY?

Back 76

DAX1 continues to repress these gene and a female embryo is created.

Loss of function mutations of SRY can produce individuals with an XY karyotype but a female phenotype.

Thus, there is very good evidence that the SRY gene is the initiator of male sexual differentiation in the embryo.

Front 77

78. Mutations in the SOX9 gene cause...?

Back 77

Can produce sex reversal (XY females) and campomelic dysplasia (malformations of bone and cartilage).

Front 78

79. What causes a male to present with a condition similar to Klinefelter's w/o increased height, with chromosome evaluation shows they have a normal female karyotype (46,XX)?

Back 78

It has been demonstrated that these XX males have an X chromosome that includes the SRY gene.

This is explained as a result of a faulty crossover between the X and Y chromosomes during male meiosis, such that the SRY gene, instead of remaining on the Y chromosome, is transferred to the X chromosome.

The offspring who inherits this X chromosome from his father consequently has a male phenotype.

Front 79

80. What does chorionic gonadotropin levels tell us?

Back 79

Urinary hCG increases when the embryo implants in the uterine wall, and thus it allows us to pinpoint accurately the occurrence of pregnancy at this early stage.

Front 80

81. What is the leading cause of pregnancy loss?

Back 80

Chromosome abnormalities.

Karyotype studies indicate that about 50% of the abnormalities are trisomies, 20% are monosomies, 15% are triploids, and the remainder consists of tetraploids and structural abnormalities.

Front 81

82. What are unbalanced or balance translocations?

Back 81

Structural chromosome abnormalities may be unbalanced (the rearrangement causes a gain or loss of chromosomal material) or balanced (the rearrangement does not produce a loss or gain of chromosome material).

Unlike aneuploidy and polyploidy, balanced structural abnormalities often do not produce serious health consequences.

Front 82

83. What is unequal crossover?

Back 82

Alterations of chromosome structure can occur when homologous chromosomes line up improperly during meiosis.

Front 83

84. What are clastogens?

Back 83

The likelihood of chromosome breakage may be increased in the presence of certain harmful agents, called clastogens.

Clastogens identified in experimental systems include ionizing radiation, some viral infections, and some chemicals.

Front 84

85. What are reciprocal translocations?

Back 84

Happens when breaks occur in two different chromosomes and the material is mutually exchanged.

The resulting chromosomes are derivative chromosomes. The carrier is usually unaffected, however, the carrier's offspring can be normal, can carry the translocation, or can have duplications or deletions of genetic material.

Front 85

86. What is an example of a reciprocal translocation?

Back 85

Partial trisomy; the karyotype is 46,XX,t(3p;6p).

The offspring of this woman received the derivative chromosome 3, termed der(3), and the normal 6; thus the child has a partial trisomy of the distal portion of chromosome 6.

Front 86

87. What are Robertsonian translocations?

Back 86

The short arms of two nonhomologous chromosomes are lost and the long arms fuse at the centromere to form a single chromosome.

This type of translocation is confined to chromosomes 13, 14, 15, 21, and 22, b/c the short arms of these acrocentric chromosomes are very small and contain no essential genetic material.

When a Robertsonian translocation takes place, the short arms are usually lost during subsequent cell divisions. B/c the carriers of Robertsonian translocations lose no essential genetic material, they are phenotypically normal but have only 45 chromosomes in each cell. Their offspring, however, may inherit a missing or extra long arm of an acrocentric chromosome.

Front 87

88. What is a common Robertsonian translocation?

Back 87

One that involves fusion of the long arms of chromosomes 14 and 21.

The karyotype of a male carrier of this translocation would be 45,XY,der(14;21)(q10;q10).

This individual lacks one normal 14 and one normal 21 and instead has a chromosome derived from a translocation of the entire long arms of chromosomes 14 and 21.

During meiosis in this individual, the translocation chromosome must still pair with its homologs.

Front 88

89. What are the two ways in which these chromosomes may segregate in the gametes formed by the translocation carrier?

Back 88

If alternate segregation occurs, then the offspring are either chromosomally normal or have a balanced translocation with a normal phenotype.

If one of the adjacent segregation patterns occurs, then the gamets are unbalanced and the offspring may have trisomy 14, monosomy 14, monosomy 21, or trisomy 21.

Fetuses w/the first three possibility do not survive to term, while the last translocation results in a Down syndrome phenotype.

Robertsonian translocations are responsible for approx 5% of Down syndrome cases.

Front 89

90. What are terminal vs. interstitial deletions?

Back 89

A single break leading to a loss that includes the chromosome's tip is called a terminal deletion.

When two breaks occur and the material between the breaks is lost, and interstitial deletion occurs.

Front 90

91. What causes Cri-du-chat syndrome?

Back 90

Caused by a deletion of the distal short arm of chromosome 5; the karyotype is 46,XY,del(5P).

Front 91

92. What is Wolf-Hirschhorn syndrome?

Back 91

Wolf-Hirschhorn syndrome is caused by a deletion of the distal short arm of chromosome 4, and is another well characterized deletion syndrome.

Other well known deletions are those of 18p, 18q, and 13q.

W/the exception of the 18p deletion syndrome, each of these disorders is relatively distinctive, and the Dx can often be made before the karyotype is obtained.

Front 92

93. What are microdeletions syndromes?

What is the best example of one?

Back 92

These deletions are often too small to be observed microscopically (i.e. less than 5 Mb).

Prader-Willi syndrome, is a good example of a microdeletion syndrome.

In total about 70% of Prader-Willi cases are caused by microdeletions of 15q.

Front 93

94. Individuals with a deletion of 11p may present with...?

Back 93

Individuals with a deletion of 11p may present w/a series of features including:
1. Wilms tumor
2. Aniridia
3. Genitourinary abnormalities (gonadoblastomas)
4. Mental retardation

AKA WAGR syndrome.

B/c WAGR syndrome involves the deletion of a series of adjacent genes, it is sometimes referred to as an example of a contiguous gene syndrome.

Front 94

95. What is Williams syndrome?

Back 94

Williams syndrome is characterized by mental retardation, supravalvular aortic stenosis (SVAS), multiple peripheral pulmonary arterial stenoses, characteristic facial features, dental malformations, and hypercalcemia.

This is another example of a microdeletion syndrome.

Front 95

96. What gene is responsible for the SVAS in Williams syndrome?

Which is responsible for the visual-spatial cognition defects observed in patients w/Williams syndrome?

Back 95

Mutations or deletions of elastin gene.

A second gene in the critical region, LIMK1, encodes a brain-expressed kinase that is likely to be involved with Williams syndrome. This is supported by the observation that patients w/partial deletions of the critical region affecting only the elastin and LIMK1 genes.

These individuals have SVAS and visual-spatial cognitive deficiency but none of the other features of Williams syndrome.

Front 96

97. What are low-copy repeats?

Back 96

Some of the microdeletion syndrome often manifest deletions of a fairly consistent portion fo a chromosome.

Recent studies show that this is caused by the presence of multiple repeated sequences, termed low-copy repeats at the deletion boundaries.

It appears that these repeated sequences promote unequal crossing over which then produces duplications and deletions of the region bounded by the repeat elements.

Front 97

98. What are subtelomeric rearrangements?

Back 97

These involve deletions or duplications of DNA in the gene-rich regions near telomeres.

Approx 7% of unexplained cases of mental retardation are caused by subtelomeric rearrangements.

Front 98

99. What is uniparental disomy?

Back 98

About 70% of Prader-Willi cases are caused by microdeletions. Most of the remaining cases involve uniparental disomy, a condition in which one parent has contributed two copies of a chromosome and the other parent has contributed none.

If the parent has contributed two copies of one homolog, the condition is termed isodisomy.

If the parent has contributed one copy of each homolog, it is termed heterodisomy.

Front 99

100. Isodisomy or heterodisomy of an imprinted chromosome can cause...?

Back 99

Prader-Willi syndrome (i.e. the inheritance of two copies from the mother and none from the father means that the individual receives no active paternal genes in the imprinted region.)

Isodisomy can result in autosomal recessive disease in the offspring of a heterozygous parent if the parent contributes two copies of the chromosome homolog that contains the disease causing mutation.

Front 100

101. What can cause uniparental disomy?

Back 100

1. A trisomic conception can lose one of the extra chromosomes, resulting in an embryo that has two copies of the chromosome contributed by one parent.

2. Can also result from the union of a gamete that contains two copies of a specific chromosome w/a gamete that contains no copies of that chromosome. In the early embryo, cells w/uniparental disomy can be produced by mitotic errors, such as chromosome loss w/subsequent duplication of the homologous chromosome.

Front 101

102. Uniparental disomy has been observed in what conditions besides Prader-Willi and Angelman syndromes?

Back 101

These include cystic fibrosis, Russell-Silver syndrome, hemophilia A, and Beckwith-Wiedemann syndrome.

Front 102

103. What are duplications?

Back 102

Duplications can arise from unequal crossover, or they can occur among the offspring of reciprocal translocation carriers.

Duplications generally produce less serious consequences than deletions do.

Includes X-linked color vision loci and Charcot-Marie-Tooth disease.

Front 103

104. What are ring chromosomes?

Back 103

Deletion sometimes occur at both tips of a chromosome. The remaining chromosome ends can then fuse, forming a ring chromosome.

The karyotype of a female with a ring X chromosome would be 46,X,r(X).

Ring chromosomes are often lost, resulting in monosomy for the chromosome in at least some cells (i.e. mosaicism for the ring chromosome may be seen).

Front 104

105. What are inversions?

Back 104

An inversion is the result of two breaks on a chromosome followed by reinsertion of the missing fragment at its original site but in inverted order.

If the inversion includes the centromere, it is called a pericentric inversion. Inversions that do not involve the centromere are termed paracentric inversions.

Parents with inversion are usually normal in phenotype but can produce offspring with deletions or duplications.

Front 105

106. What is recombinant 8 syndrome?

Back 105

A pericentric inversion on chromosome 8 (46,XX,inv[8]).

About 5% of the offspring of persons who carry this inversion will receive a deletion or duplication of the distal portion of 8q.

This combination results in the recombinant 8 syndrome, which is characterized by mental retardation, heart defects, seizures, and a characteristic facial appearance.

Front 106

107. What are isochromosomes?

What produces isochromosomes?

Back 106

Sometimes a chromosome divides along the axis perpendicular to its usual axis of division.

The result is an isochromosome, a chromosome that has two copies of one arm and no copies of the other. B/c the genetic material is substantially altered, isochromocomes of most autosomes are lethal. Most observed involve the X chromosome, and babies with isochromosome Xq usually have features of Turner syndrome.

Although most isochromosomes appear to be formed by faulty division, they can also be created by Robertsonian translocations of homologous acrocentric chromosomes.

Front 107

108. What are the four generalizations we can make about chromosome syndromes?

Back 107

1. Most chromosome abnormalities (esp those involving autosomes) are associated w/developmental delay in children and mental retardation in older individuals. This high proportion of mental difficulties suggests that a chromosome abnormalities is very likely to involve genes that affect nervous system development.
2. Most chromsome syndromes involve alterations of facial morphogenesis that produce characteristic facial features. Usually the facial features and minor anomalies of the head and limbs are the best aids to Dx.
3. Growth delay is commonly seen in autosomal syndromes.
4. Congenital malformations, especially congenital heart defects, occur with increased freq in most autosomal chromosome disorders.

Front 108

109. What are the most common clinical indications for chromosome analysis?

Back 108

A newborn with multiple congenital malformations or a child with developmental retardation.

Front 109

110. What causes CML?

Back 109

The abnormalities was identified as a reciprocal translocation between chromosomes 9 and 22.

The Philadelphia chromosome, as this translocation is commonly known, consists of a translocation of most of chromosome 22 onto the long arm of chromosome 9. A small distal portion of 9q in turn is translocated to chromosome 22.

The net effect is a smaller chromosome 22.

Front 110

111. In CML, what happens to ABL?

Back 110

A proto-oncogene called ABL is moved from its nromal position on 9q to 22q. This alters the ABL gene product, causing increased tyrosine kinase activity, which leads to malignancy in hematopoietic cells.

Front 111

112. What is another example of a translocation that produces cancer?

Back 111

Burkitt lymphoma, a childhood jaw tumor.

In this case, a reciprocal translocation involving chromosome 8 and 14 moves the MYC proto-oncogene from 8q24 to 14q32, near the immunoglobulin heavy chain loci.

There is good evidence that transcription regulation sequences near the immunoglobulin genes then activate MYC, causing malignancies to form.

Front 112

113. What are the chromosome instability syndromes?

Back 112

These syndromes all involve increased frequencies of chromosome breakage and an increased risk of malignancy. All are associated w/defects in DNA replication or repair.

These conditions include:
1. Ataxia-telangiectasia
2. Bloom syndrome
3. Fanconi anemia
4. Xeroderma pigmentosum

Front 113

114. What is the DiGeorge anomaly, and what causes it?

Back 113

Consists of structural or functional defects of the thymus, hypoparathyroidism, secondary hypocalcemia, and conotrucal heart defects.

This pattern is a malformation complex that is probably caused by an alteration of the embryonic migration of neural crest cells to the developing structures of the neck.

It was learned that some children with this syndrome had a deletion of part of the long arm of chromosome 22.

Front 114

115. What is velocardiofacial or Shprintzen syndrome?

Back 114

This autosomal dominant syndrome involves palate (velum) abnormalities (including clefts), a characteristic facial appearance, and, in some cases, heart disease. In addition, these patients have learning disabilities and developmental delay.

Later it was discovered that some individuals with VCF have dysfunctional T-cells and some have all features of the DiGeorge anomaly.

Front 115

116. How are VCF syndrome and the DiGeorge anomaly related?

Back 115

Patients with DiGeorge and patients with VCF revealed small deletions of chromosome 22 in both groups.

Approx 90% of individuals with DiGeorge have a 22q11.2 microdeletion, and about 70% of VCF patients have the same microdeletion.

The VCF syndrome is a contiguous gene syndrome, and it is possible that the gene or genes causing the DiGeorge anomaly are a subset of those that cause VCF.

Front 116

117. In the developing down syndrome brain, is there up-regulation or down-regulation of the extra copy of chromosome 21?

Back 116

New studies suggest that there is global up-regulation of chromosome 21 gene expression in the developing down syndrome brain.

Front 117

118. What psychiatric disorders are patients with the 22q11.2 deletion syndrome at particularly high risk?

Back 117

Schizophrenia and bipolar disorders.

In fact, it is estimated that 25% of adults with this syndrome develop schizophrenia.

Front 118

119. Patients with Klinefelter syndrome are at an increased risk for developing...?

Back 118

1. Breast cancer
2. Extragonadal germ cell tumors
3. Autoimmune diseases such as SLE (presumably due to low testosterone levels and high estrogen levels)

Front 119

120. What is a true hermaphrodite vs. a pseudohermaphrodite?

Back 119

A true hermaphrodite implies the presence of both ovarian and testicular tissue, where as a pseudohermaphrodite represents a disagreement between the phenotypic and gonadal sex (i.e. a female pseudohermaphrodite has ovaries but male external genitalia; a male pseudohermaphrodite has testicular tissue but female-type genitalia.

Front 120

121. What are the characteristics of a true hermaphrodite?

Back 120

Very rare. These individuals have both ovaries and testes, either combined as an ovotestis or with one gonad on each side.

50% have 46,XX karyotype; of the remaining, approx equal numbers have 46,XY and 45,X/46,XY karyotypes.

Front 121

122. What are the characteristics of a female pseudohermaphrodite?

Back 121

Female pseudohermaphrodites have a 46,XX karyotype. Ovaries and internal genitalia are normal, but external genitalia are ambiguous or virilized.

The most common cause is inappropriate exposure to androgenic steroids during gestation. The condition may occur in congenital adrenal hyperplasia or in the presence of androgen-secreting maternal tumors.

Front 122

123. What are the characteristics of a male pseudohermaphrodite?

Back 122

Male pseudohermaphrodites have Y chromosomes; the gonads are therefore exclusively testes, but external genitalia are either ambiguous or completely female.

The condition results from defective virilization of the male embryo b/c of reduced androgen synthesis or resistance to action of androgens.

The most common form is complete testicular feminization (androgen insensitivity syndrome) associated with mutation in the structural gene for the androgen receptor located on Xq11-Xq12.

Front 123

124. What are the symptoms of fragile-X syndrome?

Back 123

1. Mental retardation
2. IQ range of 20-60
3. Long face with a large mandible
4. Large everted ears
5. *Large testicles (macro-orchidism)

*The only distinctive feature that can be detected in at least 90% of postpubertal males w/fragile X syndrome is macro-orchidism.

Front 124

125. What is the cause of fragile X syndrome?

Back 124

It is characterized cytogenetically by a fragile site on Xq27.3, which is visualized as a discontinuity of chromosomal staining.

At this site, there are multiple tandem repeats of the nucleotide sequence CGG in the 5'-untranslated region of the FMR-1 gene

Front 125

126. Why is mental retardation present in most male offspring, and only in 50% of female offspring with Fragile X syndrome?

Back 125

When the premutation is passed on by a carrier female, however, there is a high probability of dramatic amplification of the CGG repeats, leading to mental retardation in most male offspring, and only in 50% of female offspring.

Thus, it appears that during the process of oogenesis, but not spermatogenesis, premutations can be converted to mutations by triplet-repeat amplification.

Front 126

127. What is FMRP?

Back 126

Familial mental retardation protein; it is a widely expressed cytoplasmic protein most abundant in the brain and testes.

FMRP is transported from the cytoplasm to the nucleus, where it assembles into an mRNP complex, thereby binding specific RNA transcripts and proteins. From here, the complexes are shuttled into the axon as well as the dendrites, close to the synapses. It is at the synapses that the FMRP-mRNP complex seems to perform a key role in regulating the translation of specific mRNAs.

It is the absence of such FMRP-mediated regulation that interferes with synaptic transmission and ultimately causes mental retardation.

Front 127

128. What are polyglutamine diseases?

Back 127

These diseases are characterized by progressive neurodegeneration, typically striking in mid life. They are caused by mutations that affect coding regions

Polyglutamine expansions lead to a toxic gain of function. The abnormal proteins aggregate in the nucleus to produce inclusions.

Front 128

129. What happens when expansions affect noncoding regions?

Back 128

The resulting mutations are loss of function type, since protein synthesis (i.e. FMRP) is suppressed.

Typically such disorders affect many systems. Many noncoding repeat disorders are characterized by a pool of intermediate size expansions or premutations, that expand to full mutations in germ cells.

Front 129

130. What is Leber hereditary optic neuropathy?

Back 129

This disease is associated with mitochondrial inheritance.

This is a neurodegenerative disease that manifests itself as progressive bilateral loss of central vision. Visual impairment is first noted between ages 15 and 35, and it leads to blindness.

Cardiac conduction defects and minor neurologic manifestations have also been observed in some families.

Front 130

131. What is the UBE3A gene linked with?

Back 130

There is a firm link between the UBE3A gene and Angelman syndrome.

This gene, called UBE3A, is a ubiquitin protein-ligase that has a role in the ubquitin-proteosome proteolytic pathway.

Front 131

132. What are the four indications for prenatal chromosome analysis?

Back 131

1. Advanced maternal age (>34 years)
2. A parent who is a carrier of a balanced reciprocal translocation, robertsonian translocation, or inversion
3. A parent with a previous child w/a chromosomal abnormality
4. A parent who is a carrier of an X-linked genetic disorder (to determine fetal sex).

Front 132

133. What are the indications for postnatal chromosome analysis?

Back 132

1. Multiple congenital anomalies
2. Unexplained mental retardation or developmental delay
3. Suspected aneuploidy (e.g. Down syndrome)
4. Suspected unbalanced autosome (e.g. Prader-Willi)
5. Suspected sex chromosomal abnromality (e.g. Turner syndrome)
6. Suspected fragile X syndrome
7. Infertility
8. Miltiple spontaneous abortions

Front 133

134. Direct gene diagnosis and Factor V

Back 133

One technique relies on the fact that some mutations alter or destroy certain restriction sites on DNA; this occurs in the gene encoding factor V.

This protein is involved in the coagulation pathway, and a mutation affecting the factor V gene is the most common cause of inherited predisposition to thrombosis.

Exon 10 of the factor V gene and the adjacent intron have two Mnl1 restriction sites. A G-to-A mutation within the exon destroys one of the two Mnl1 sites.

To detect the mutant gene, two primers that bind to the 3' and 5' prime ends of the normal sequence are designed. By using appropriate DNA polymerases and thermal cycling, the DNA between the primers is greatly amplified, producing millions of copies of the DNA between the two primer sites. The amplified normal DNA and patient's DNA are then digested with the Mnl1 enzyme. Under these conditions, the normal DNA yields three fragments (67 base pairs, 37 base pairs, and 163 base pairs long); by contrast, the patient's DNA yields only two products, an abnormal fragment that is 200 base pairs and a normal fragment that is 67 base pairs long. These DNA fragments can be readily resolved by polyacrylamide gel electrophoresis and then visualized after staining with ethidium bromide under ultraviolet light.

Front 134

135. Storage and journey of sperm #1

Back 134

The testes is composed of up to 900 coiled seminiferous tubules, each averaging more than one half meter long, in which the sperm are formed.

The sperm then empty into the epididymis, another coiled tube about 6 m long. The epididymis leads into the vas deferens, which enlarges into the ampulla of the vas deferens immediately before the vas enters the body of the prostate gland.

Front 135

136. Storage and journey of sperm #2

Back 135

Two seminal vesicles, one located on each side of the prostate, empty into the prostatic end of the ampulla, and the contents from both the ampulla and the seminal vesicles pass into an ejaculatory duct leading through the body of the prostate gland and then emptying into the internal urethra.

Prostatic ducts, too, empty from the prostate gland into the ejaculatory ducts and from there into the prostatic urethra.

Front 136

137. What is the process of spermatogenesis?

Back 136

1. During formation of the embryo, the primordial germ cells migrate into the testes and become immature germ cells called spermatogonia, which lie in two or three layers of the inner surfaces of the seminiferous tubules.

2. The spermatogonia begin to undergo mitotic division, beginning at puberty, and continually proliferate and differentiate through definite stages of development.

Front 137

138. What are the steps of spermatogenesis?

Back 137

1. The spermatogonia migrate among Sertoli cells toward the central lumen of the seminiferous tubule. The Sertoli cells are large, with overflowing cytoplasmic envelopes that surround the developing spermatogonia all the way to the central lumen of the tubule.

2. Spermatogonia that cross the barrier into the Sertoli cells layer become progressively modified and enlarged to form large primary spermatocytes. Each of these in turn undergoes meitotic division to form two secondary spermatocytes. After another few days, these also divide to form spermatids.

Front 138

139. What enzymes are contained within the acrosome?

Back 138

A number of enzymes similar to those found in lysosomes of the typical cells, including hyaluronidase (which can digest proteoglycan filaments of tissues) and powerful proteolytic enzymes (which can digest proteins).

Front 139

140. What are the three major components of the flagellum of the sperm?

Back 139

1. A central skeleton constructed of 11 microtubules, collectively called the axoneme
2. A thin cell membrane covering the axoneme
3. A collection of mitochondria surrounding the axoneme in the proximal portion of the tail (called the body of the tail)

Front 140

141. Movement of the sperm is caused by...?

Back 140

Movement of the tail (flagellar movement) provides motility; this movement results from a rhythmical longitudinal sliding motion between the anterior and poasterior tubules that make up the axoneme.

The energy for this process is supplied in the form of ATP that is synthesized from the mitochondria in the body of the tail.

Front 141

142. What are the 5 hormones that stimulate spermatogenesis?

Back 141

1. Testosterone
2. LH
3. FSH
4. Estrogens
5. GH

Front 142

143. What is testosterone's role in spermatogenesis?

Back 142

Testosterone, secreted by the Leydig cells located in the interstitium of the testis, is essential for growth and division of the testicular germinal cells, which is the first stage in forming sperm.

Front 143

144. What is LH's role in spermatogenesis?

Back 143

LH, secreted by the anterior pituitary, stimulates the Leydig cells to secrete testosterone

Front 144

145. What is FSH's role in spermatogenesis?

Back 144

FSH, also secreted by the anterior pituitary, stimulates the Sertoli cells; without this stimulation, the conversion of the spermatids to sperm will not occur (spermiogenesis)

Front 145

146. What is estrogen's role in spermatogenesis?

Back 145

Estrogens, formed from testosterone by the Sertoli cells when they are stimulated by FSH, are probably also essential for spermiogenesis.

Front 146

147. What is GH's role in spermatogenesis?

Back 146

GH is necessary for controlling background metabolic functions of the testes.

GH specifically promotes early division of the spermatogonia themselves; in its absence, as in pituitary dwarfs, spermatogenesis is severely deficient or absent, thus causing infertility.

Front 147

148. Where do the sperm mature?

Back 147

In the epididymis. Sperm removed from the seminiferous tubules and from the early portions of the epididymis are nonmotile, and they cannot fertilize and ovum.

However, after the sperm have been in the epididymis for some 18-24 hours, they develop the capability of motility, even though several inhibitory proteins in the epididymal fluid still prevent final motility until after ejaculation.

Front 148

149. Where is sperm stored and for how long?

Back 148

The two testes form up to 120 million sperm each day. A small quantitiy of these can be stored in the epididymis, but most are stored in the vsa deferens.

They can remain stored, maintaining their fertility, for at least a month. During this time, they are kept in a deeply suppressed inactive state by multiple inhibitory substances in the secretions of the ducts.

Front 149

150. How do sperm become mobile after ejaculation?

Back 149

The Sertoli cells and the epithelium of the epididymis secrete a special nutrient fluid that is ejaculated along with the sperm. This fluid contains hormones including testosterone and estrogens, enzymes, and special nutrients that are essential for sperm maturation.

Front 150

151. How fast can the mature sperm move?

Back 150

The normal, fertile sperm are capable of flagellated movement thru fluid medium at velocities of 1-4 mm/min.

The acitivty of the sperm is greatly enhanced in a neutral and slightly alkaline medium, as exists in the ejaculated semen, but it is greatly depressed in a mildly acidic medium.

A strong acidic medium can cause rapid death of sperm.

Front 151

152. What is the function of the seminal vesicles?

Back 151

Each seminal vesicle is a tube lined with a secretory epithelium that secretes a mucoid material containing an abundance of fructose, citric acid, and other nutrient substances as well as large quantities of prostaglandins and fibrinogen.

During ejaculation, each vesicle empties its contents into the ejaculatory duct shortly after the vas deferens empties the sperm. This adds greatly to the bulk of the semen and the fructose and other substances in the seminal fluid are of considerable nutrient value for the ejaculated sperm.

Front 152

153. In what two way are prostaglandins believed to aid fertilization?

Back 152

1. By reacting with the female cervical mucus to make it more receptive to sperm movement

2. By possible causing backward, reverse peristaltic contractions in the uterus and fallopian tubes to move the ejaculated sperm toward the ovaries (a few sperm reach the upper ends of the fallopian tubes within 5 minutes).

Front 153

154. What is the function of the prostate gland?

Back 153

The prostate secretes a thin, milky fluid that contains calcium, citrate ion, phosphate ion, a clotting enzyme, and a profibrinolysin.

During emission, the prostate contracts and the thin, milky fluid adds further to the bulk of the semen.

A slightly alkaline characteristic of the prostatic fluid may be important for successful fertilization of the ovum, b/c the fluid of the vas deferens is relatively acidic owing to the presence of citric acid and metabolic end products of the sperm, and, consequently, helps to inhibit sperm fertility.

Front 154

155. pH of vagina and semen

Back 154

The vaginal secretions of the female are acidic (pH of 3.5 - 4.0). Sperm do not become optimally motile until the pH of the surrounding fluids rises to about 6.0 to 6.5.

Consequently, it is likely that the slightly alkaline prostatic fluid helps to neutralize the acidity of the other seminal fluids during ejaculation and thus enhances the motility and fertility of the sperm.

The average pH of semen is about 7.5.

Front 155

156. Composition of semen

Back 155

Semen contains fluid from the vas deferens (10%), fluid from the seminal vesicles (60%), fluid from the prostate( 30%), and small amts from the mucous glands, especially the bulbourethral glands.

Thus, the bulk of the semen is seminal vesicle fluid, which is the last to be ejaculated and serves to wash the sperm through the ejaculatory duct and urethra.

Front 156

157. Clotting enzyme and profibrinolysin function

Back 156

A clotting enzyme from the prostatic fluid causes the fibrinogen of the semen to form a weak fibrin coagulum that holds the semen in the deeper regions of the vagina where the uterine cervix lies.

The coagulum then dissolves during the next 15 to 30 minutes b/c of lysis by fibrinolysin formed form the prostatic profibrinolysin.

Front 157

158. What is capacitation?

Back 157

When sperm are first expelled in the semen, they are unable to perform their duties in fertilizing the ovum.

However, on coming in contact w/the fluids of the female genital tract, multiple changes occur that activate the sperm for the final processes of fertilization.

This is called capacitation.

Front 158

159. What are the three changes that occur during capacitation?

Back 158

1. The uterine and fallopian tube fluids wash away various inhibitory factors that suppress sperm activity in the male genital tracts
2. In the male genital ducts, the sperm are surrounded by cholesterol vesicles, which are continuously added to the cellular membrane covering the sperm acrosome, toughening the membrane and preventing release of its enzymes. After ejaculation, the sperm lose much of their excess cholesterol. In doing so, the membrane at the head of the sperm becomes much weaker.
3. The membrane of the sperm also becomes more permeable to calcium ions, so that calcium now enters the sperm in abundance and changes the activity of the flagellum, giving it a powerful whiplash motion. The calcium ions also make the acrosome more able to release its enzymes.

Front 159

160. What do the enzymes in the acrosome do?

Back 159

Stored in the sperm are large quantities of hyaluronidase and proteolytic enzymes.

Hyaluronidase depolymerizes the hyaluronic acid polymers in the intercellular cement that holds the ovarian granulosa cells together. The proteolytic enzymes digest proteins in the structural elements of tissue cells that still adhere to the ovum.

Front 160

161. What is the acrosome reaction?

Back 160

When the ovum is expelled from ovarian follicles into the fallopian tube, it still carries with it multiple layers of granulosa cells.

Before a sperm can fertilize the ovum, it must dissolute these granulosa cell layers, and then it must penetrate through the thick covering of the ovum itself, the zona pellucida.

To achieve this, the stored enzymes in the acrosome begin to be released. It is believed that the hyaluronidase among these enzymes is especially important in opening pathways between the granulosa cells so that the sperm can reach the ovum.

Front 161

162. What occurs during the acrosome reaction and fertilization?

Back 161

When the sperm reach the zona pellucida, the anterior membrane of the sperm itself binds specifically with receptor proteins in the zona pellucida.

Then, rapidly, the entire acrosome dissolves, and all the enzymes are released.

Within minutes, these enzymes open a penetrating pathway for passage of the sperm head through the zona pellucida to the inside of the ovum.

Within another 30 minutes, the cell membranes of the sperm head and of the oocyte fuse with each other to form a single cell.

Front 162

163. Why does only one sperm enter the occyte?

Back 162

Within a few minutes after the first sperm penetrates the zona pellucida of the ovum, calcium ions diffuse inward thru the oocyte membrane and cause multiple cortical granules to be released by exocytosis from the oocyte into the perivitelline space.

These granules contain substances that permeate all portions of the zona pellucida and prevent binding of additional sperm, and they even cause any sperm that have already begun to bind to fall off.

Front 163

164. What are some things that can destroy the seminiferous tubular epithelium?

Back 163

Bilateral orchitis of the testes resulting from mumps causes sterility in some males. Also, some male infants are born with degenerate tubular epithelia as a result of strictures in the genital ducts or other abnormalities.

Excessive temperatures can also cause this.

Front 164

165. What is crytorchidism?

Back 164

Means failure of a testis to descend form the abdomen into the scrotum at or near the time of birth of a fetus.

A testis that remains in the abdomen cannot form sperm. The tubular epithelium becomes degenerate, leaving only the interstitial structures of the testis. This can be due to increased temps in the abdominal cavity.

Front 165

166. Role of testosterone in testes descent

Back 165

Testosterone secretion by the fetal testes themselves is the normal stimulus that causes the testes to descend into the scrotum from the abdomen.

Therefore, many, if not most, instances of crytorchidism are caused by abnormally formed testes that are unable to secrete enough testosterone. The surgical operation for crytorchidism in these patients is unlikely to be successful.

Front 166

167. What is the effect of sperm count on fertility?

Back 166

An average of 400 million sperm are usually present in the several mLs of ejaculate.

When the number of sperm in each mL of semen falls below 20 million, the person is likely to be infertile.

Front 167

168. What are the important sensory nerve signals in the male sexual act?

Back 167

The most important source of sensory nerve signals for initiating the male sexual act is the glans penis. Signals from the glans pass through the pudendal nerve then through the sacral plexus into the sacral portion of the spinal cord, and finally up the cord to the brain.

Impulses may also enter the spinal cord from stimulation of the anal epithelium, the scrotum, and perineal structures.

Front 168

169. How does cantharidin act as an aphrodisiac?

Back 168

One of the causes of sexual drive is filling of the sexual organs with secretions.

Mild infection and inflammation of these organs sometimes cause almost continual sexual desire.

Drugs, such as cantharidin, increase sexual desire by irritating the bladder and urethral mucosa, inducing inflammation and vascular congestion.

Front 169

170. Psychic component of male sexual stimulation

Back 169

Simply thinking sexual thoughts or even dreaming can initiate the male act.

Front 170

171. What is the integration of the male sexual act in the spinal cord?

What causes the male orgasm?

Back 170

Although psychic factors play a role in the male sexual act, brain function is probably not necessary for its performance b/c appropriate genital stimulation can cause ejaculation in some animals and occasionally in humans after their spinal cords have been cut above the lumbar region.

The male sexual act results from inherent reflex mechanisms integrated in the sacral and lumbar spinal cord, and these mechanisms can be initiated by either psychic stimulation from the brain or actual sexual stimulation from the sex organs.

Front 171

172. How does an erection occur?

Back 171

Parasympathetics impulses pass from the sacral portion of the spinal cord through the pelvic nerves to the penis.

The parasympathetic nerve fibers are believed to release NO and/or vasoactive intestinal peptide in addition to ACh.

The NO especially relaxes the arteries of the penis, as well as relaxes the trabecular meshwork of smooth muscle fibers int he erectile tissue of the corpora cavernosa and corpus spongiosum.

Front 172

173. Does the male sex organs facilitate lubrication?

Back 172

Yes, the parasympathetic impulses, in addition to promoting erection, cause the urethral glands and the bulbourethral glands to secrete mucus.

This mucus flows through the urethra during intercourse to aid in lubrication.

Front 173

174. What causes orgasm?

Back 173

When the sexual stimulus becomes intense, the reflex centers of the spinal cord emit sympathetic impulses that leave the cord at T12-L2 and pass to the genital organs thru the hypogastric and pelvic sympathetic nerve plexuses to initiate emission, the forerunner of ejaculation.

Front 174

175. What is emission?

Back 174

Emission begins with contraction of the vas deferens and the ampulla to cause expulsion of sperm into the internal urethra. Then, contractions of the muscular coat of the prostate gland followed by contraction of the seminal vesicles expel prostatic and seminal fluid also into the urethra, forcing the sperm forward.

All these fluids mix in the internal urethra with mucus already secreted by the bulbourethral glands to form the semen.

Front 175

176. What hormone is secreted by the interstitial cells of Leydig in the testes?

Back 175

Testosterone is formed by the interstitial cells of Leydig.

Front 176

177. Where else are androgens secreted in the body?

Back 176

The adrenal glands secrete at least five androgens, although the total masculinizing activity of these is normally so slight that even in women they do not cause virilization except for growth of pubic and axillary hair.

But when an adrenal tumor of the adrenal androgen producing cells occurs, virilization can occur.

Also, the normal ovary also produces minute quantities of androgens, but they are not significant.

Front 177

178. What are arrhenoblastomas?

Back 177

Rarely, embryonic rest cells in the ovary can develop into a tumor that produces excessive quantities of androgens in women; one such tumor is the arrhenoblastoma.

Front 178

179. What is the metabolism of testosterone?

Back 178

After secretion, about 97% of the testosterone becomes either bound loosely with plasma albumin or more tightly bound w/a beta globulin called sex hormone binding globulin and circulates in the blood in these states for 30 min to several hours. By that time, the testosterone is either transferred to the tissues or is degraded into inactive products that are subsequently excreted.

Front 179

180. What is testosterone in the tissues converted to?

What happens if it is not fixed in the tissues?

Back 179

Much of the testosterone that becomes fixed to the tissues is converted within the tissue cells to dihydrotestosterone, especially in the prostate and external genitalia of the male fetus.

When it does not become fixed to the tissues, it is rapidly converted, mainly by the liver, into androsterone and dehydroepiandrosterone (DHEA) and simultaneously conjugated as either glucuronides or sulfates. These are excreted either into the gut by way of the liver bile or into the urine through the kidneys.

Front 180

181. Where are estrogens produced in the male?

Back 180

1. The concentration of estrogens in the fluid of the seminiferous tubules is quite high and probably plays a role in spermiogenesis. This estrogen is believed to be formed by the Sertoli cells by converting testosterone to estradiol.

2. Much larger amts of estrogens are formed from testosterone and androstanediol in other tissues of the body, probably accounting for as much as 80% of the total male estrogen production.

Front 181

182. What are the functions of testosterone during fetal development?

Back 181

Testosterone is secreted first by the genital ridges and later by the fetal testes and is responsible for the development of the male body characteristics.

Testosterone begins to be secreted by the testes at about the 7th week of embryonic life.

Also, it causes formation of the prostate, seminal vesicles, and male genital ducts, while at the same time suppressing the formation of female genital organs.

Front 182

183. When do the testes descend?

Back 182

The testes usually descend into the scrotum during the last 2-3 months of gestation when the testing secrete large amts of testosteorone.

If they do not descend, administration of exogenous testosterone can usually cause the testes to descend.

Also, administration of gonadotropic hormones, which stimulate the Leydig cells to produce testosterone can also cause the testes to descend.

Front 183

184. What is the relationship between baldness and testosterone?

Back 183

Testosterone decreases the growth of hair on the top of the head. However, many virile men never become bald b/c baldness is a result of two factors, a genetic background and large quantities of androgenic hormones.

A woman who has the appropriate genetic background and who develops a long sustained androgenic tumor becomes bald.

Front 184

185. Testosterone and muscle development

Back 184

One of the most important male characteristics is development of increasing musculature after puberty, averaging about a 50% increase in muscle mass over that in the female.

This is associated w/increased protein in the nonmuscle parts of the body as well.

Front 185

186. What is the effect of testosterone on bones?

Back 185

Testosterone increased bone matrix and causes calcium retention.

The increase in bone matrix is believed to result from the general protein anabolic function of testosterone plus deposition of calcium salts in response to the increased protein.

B/c of the ability of testosterone to increase the size and strength of bones, it is often used in older men to treat osteoporosis.

Front 186

187. What are the four changes that testosterone causes in the shape of the pelvis?

Back 186

1. Narrows the pelvic outlet
2. Lengthens it
3. Causes a funnel like shape instead of the broad ovoid shape of the female pelvis
4. Greatly increases the strength of the entire pelvis for load bearing

Front 187

188. What is the effect of testosterone on basal metabolism?

Back 187

Testosterone increases basal metabolism by as much as 15%.

This increased rate of metabolism is possibly an indirect result of the effect of testosterone on protein anabolism, the increased quantity of proteins, the enzymes especially, increasing the activities of all cells.

Front 188

189. What is the effect of testosterone on RBCs?

Back 188

Testosterone increases the number of RBCs in the blood.

This increase may be due partly to the increase metabolic rate that occurs after testosterone administration rather than to a direct effect of testosterone on RBC production.

Front 189

190. What is the effect of testosterone on electrolyte and water balance?

Back 189

Many steroid hormones can increase the reabsorption of sodium in the distal tubules of the kidneys.

Testosterone also has such an effect, but only to a minor degree in comparison with the adrenal mineralocorticoids.

Nevertheless, after puberty, the blood and ECF volumes of the male in relation to body weight increases as much as 5-10%.

Front 190

191. What is the basic intracellular mechanism of action of testosterone?

Back 190

Most of the effects of testosterone result basically from increased rate of protein formation in the target cells.

In the prostate gland, testosterone enters the prostatic cells within a few minutes after secretion. Then it is most often converted, under the influence of the intracellular enzyme 5α-reductase, to dihydrotestosterone, and this in turn binds with a cytoplasmic “receptor protein.”

Front 191

192. What happens when the converted testosterone binds to the receptor protein?

Back 191

This combination migrates to the cell nucleus, where it binds with a nuclear protein and induces DNA-RNA transcription.

Within 30 minutes, RNA polymerase has become activated and the concentration of RNA begins to increase in the prostatic cells; this is followed by progressive increase in cellular protein. After a couple days, the quantity of DNA in the prostate gland has also increased and there has been a simultaneous increase in the number of prostatic cells.

Front 192

193. What hormones control male sexual function?

Back 192

Begins with secretion of GnRH by the hypothalamus.

This hormone then stimulates the anterior pituitary gland to secretion LH and FSH.

In turn, LH is the primary stimulus for the secretion of testosterone by the testes, and FSH mainly stimulates spermatogenesis.

Front 193

194. Where is GnRH secreted, and how is it secreted?

What are the two ways in which the intensity of the hormone's stimulus is determined?

Back 193

GnRH is secreted by neurons whose cells bodies are located in the arcuate nuclei of the hypothalamus.

GnRH is secreted intermittently a few minutes at a time once very 1-3 hours.

The intensity of the hormone's stimulus is determined in two ways:
1. By the freq of these cycles of secretion
2. By the quantity of GnRH released w/each cycle

Front 194

195. Secretion of FSH and LH - what is the frequency?

Back 194

The secretion of LH by the anterior pituitary is also cyclical, with LH following fairly faithfully the pulsatile release of GnRH.

Conversely, FSH secretion increases and decreases only slightly w/each fluctuation of GnRH secretion; instead, it changes more slowly over a period of many hours in response to longer-term changes in GnRH.

Front 195

196. How do LH and FSH exert their effects on their target tissues in the testes?

Back 195

Mainly by activating the cAMP second messenger system, which in turn activates specific enzyme systems in the respective target cells.

Front 196

197. Testosterone secretion and LH

Back 196

Testosterone is secreted by the interstitial cells of Leydig in the testes, but only when they are stimulated by LH.

Furthermore, the quantity of testosterone secreted increases approximately in direct proportion to the amt of LH available.

Front 197

198. How does testosterone affect anterior pituitary secretion of LH and FSH?

Back 197

The testosterone secreted by the testes in response to LH has the reciprocal effect of inhibiting anterior pituitary secretion LH.

Most of this inhibition probably results from a direct effect of testosterone on the hypothalamus to decrease secretion of GnRH.

This in turn causes a corresponding decrease in secretion of both LH and FSH by the anterior pituitary, and the decrease in LH reduces the secretion of testosterone by the testes.

Conversely, too little testosterone allows the hypothalamus to secrete large amts of GnRH.

Front 198

199. Regulation of spermatogenesis is done by...?

Back 198

FSH and testosterone.

FSH binds w/specific FSH receptors attached to the Sertoli cells in the seminiferous tubules. This causes these cells to grow and secrete various spermatogenic substances.

Simultaneously, testosterone and dihydrotestosterone diffusing into the seminiferous tubules from the Leydig cells in the interstitial spaces also has a strong tropic effect on spermatogenesis.

Front 199

200. What is the hormone inhibin?

Back 199

When the seminiferous tubules fail to produce sperm, secretion of FSH increases markedly. Conversely, when spermatogenesis proceeds too rapidly, pituitary secretion of FSH diminishes.

The cause of this negative feedback effect on the anterior pituitary is believed to be secretion by the Sertoli cells of a hormone called inhibin.

This hormone has a strong direct effect on the anterior pituitary gland to inhibit the secretion of FSH and possibly a slight effect on the hypothalamus to inhibit secretion of GnRH.

Front 200

201. What is the role of hCG from the placenta?

Back 200

During pregnancy, if the fetus is a male, hCG from the placenta causes the testes of the fetus to secrete testosterone.

Front 201

202. What is the male climacteric?

Back 201

Most men begin to exhibit slowly decreasing sexual functions in there late 40-50's.

This decline in sexual function is related to decrease in testosterone secretion. This climacteric is associated with symptoms of hot flashes, suffocation, and psychic disorders similar to the menopausal woman.

Front 202

203. What is a benign prostatic fibroadenoma?

Back 202

A benign prostatic fibroadenoma freq develops in the prostate in many older men and can cause urinary obstruction. This hypertrophy is caused by abnormal overgrowth of the prostate tissue itself, NOT by testosterone.

Front 203

204. Prostate cancer

Back 203

Cancer of the prostate gland is a different problem and is a common cause of death, accounting for about 2 to 3 per cent of all male deaths. Once cancer of the prostate gland does occur, the cancerous cells are usually stimulated to more rapid growth by testosterone and are inhibited by removal of both testes so that testosterone cannot be formed.

Prostatic cancer usually can be inhibited by administration of estrogens. Even some patients who have prostatic cancer that has already metastasized to almost all the bones of the body can be successfully treated for a few months to years by removal of the testes, by estrogen therapy, or by both; after this therapy the metastases usually diminish in size and the bones partially heal. This treatment does not stop the cancer but does slow it and sometimes greatly diminishes the severe bone pain.

Front 204

205. What is adiposogenital syndrome?

Back 204

Some instances of hypogonadism are caused by a genetic inability of the hypothalamus to secrete normal amounts of GnRH.

This is often associated with a simultaneous abnormality of the feeding center of the hypothalamus causing the person to greatly overeat.

Consequently, obesity occurs along with eunuchism. This is called adiposogenital syndrome, Frohlich's syndrome, or hypothalamic eunuchism.

Front 205

206. What are interstitial Leydig cell tumors?

Back 205

These tumors are rare, but when they develop, they produce as much as 100 times the normal quantities of testosterone.

When such tumors develop in young children, they cause rapid growth of the musculature and bones but also cause early uniting of growth plates so they are shorter.

Such interstitial cells tumors also cause excessive development of the the male sexual organs, all skeletal muscles, and other male sexual characteristics.

Front 206

207. What is the role of the pineal gland?

Back 206

The pineal gland plays a regulatory role in sexual and reproductive function.

The pineal gland is controlled by the circadian rhythm. The nervous pathway involves the passage of light signals from the eyes to the suprachiasmal nucleus of the hypothalamus and then to the pineal gland, activating pineal secretion.

Also, the pineal gland secreted melatonin; either melatonin or another substance secreted by the pineal gland pass to the fluid of the third ventricle to the anterior pituitary to decrease gonadotropic hormone secretion.

Front 207

208. Summary of pineal gland role

Back 207

Thus, in the presence of pineal gland secretion, gonadotropic hormone secretion is suppressed in some specifies of animals, and the gonads become inhibited and even partly involuted.

This explains the seasonal mating behaviors in other animals.

Front 208

209. What does 5α-reductase do?

Back 208

Testosterone is converted in target issues to the more active dihydrotestosterone, which binds to the androgen receptor with an affinity 10x higher than that of testosterone.

The formation of dihydrotestosterone from testosterone is catalyzed by 5α-reductase.

Front 209

210. What is the most common and potent estrogen?

Back 209

17β-estradiol

Front 210

211. What enzyme converts androgens to estrogens, and where is this conversion most active?

Back 210

All estrogens are derived from the aromatization of precursor androgens.

The ovary and placenta most actively synthesize the aromatase enzyme that converts androgens to estrogens, but other non-reproductive tissues such as adipose tissue, hypothalamic neurons and muscle can also aromatize androgens to estrogen.

Front 211

212. What are the roles of inhibin A, B, and activin?

Back 211

Inhibins secreted by the gonad act on the anterior pituitary gland to inhibit the release of FSH, while activin stimulates FSH release.

Neither the inhibits nor activin has an effect on anterior pituitary release.

Front 212

213. What is the polycystic ovarian syndrome (PCOS)?

Back 212

PCOS is a complex syndrome characterized by anovulation and by increased levels of plasma androgen.

PCOS is a common problem affecting between 3-5% of women of reproductive age.

All etiologies of this disease result in increased androgen secretion and suppression of normal ovulatory cycles. The increased androgen secretion results in masculinization.

Front 213

214. What is the first of the three primary hypotheses that attempt to explain the development of PCOS?

Back 213

LH hypothesis: many women w/PCOS have and increase frequency and amplitude of pituitary LH pulses. Increased LH activity stimulates thecal cells of the ovary to synthesize increased amts of androgens, including androstenedione and testosterone.

In addition, increased LH and androgens prevent normal follicle growth, in turn preventing follicle secretion of large amts of estrogen.

The absence of an estrogen trigger prevents the LH surge and ovulation.

Front 214

215. What is the second of the three primary hypotheses that attempt to explain the development of PCOS?

Back 214

Insulin theory: based on the observation that many women w/PCOS are obese and insulin resistant and secrete increased insulin.

Increased insulin decreases the production of sex hormone binding globulin (SHBG), which result sin a higher concentration of free testosterone and therefore greater androgenic effects on peripheral tissues.

It has also been observed that insulin can directly synergize w/LH to increase androgen production by thecal cells.

Interestingly, in women w/PCOS, medications that specifically treat insulin resistance, i.e. metformin, may result in regular ovulatory menses and normalization of testosterone levels.

Front 215

216. What is the last of the three primary hypotheses that attempt to explain the development of PCOS?

Back 215

Ovarian hypothesis: This explanation posits dysregulation of sex steroid synthesis at the level of the thecal cell.

For example, an abnormal increase in the activity of the oxidative enzymes responsible for androgen synthesis could lead to greater thecal cell production of androgens in response to any given stimulus.

Front 216

217. What are the inhibitors of gonadal hormones (the GnRH agonists and antagonists)?

Back 216

GnRH agonists:
1. Gonadorelin
2. Goserelin
3. Histrelin
4. Leuprolide
5. Nafarelin

Antagonists:
1. Cetrorelix
2. Ganirelix

Front 217

218. GnRH Agonists:
1. Gonadorelin
2. Goserelin
3. Histrelin
4. Leuprolide
5. Nafarelin

Back 217

MOA: Continuous: inhibit LH and FSH release; pulsatile - stimulate LH and FSH release

PURPOSE: Hormone dependent tumors such as prostate cancer, and in some cases breast cancer

Front 218

219. What are the 5α-reductase inhibitors, and how do they work?

Back 218

Finasteride is a selective inhibitor of type II 5α-reductase, the enzyme that converts testosterone to dihydrotestosterone.

Blocking the local conversion of testosterone to dihydrotestosterone effectively abrogates the local action of testosterone.

Prostate cells are dependent on androgen stimulation for survival, and administration of a reductase inhibitor slows the growth of prostate tissue.

Front 219

220. Finasteride

Back 219

MOA: Selective inhibitor of type II 5α-reductase, the enzyme that converts testosterone to dihydrotestosterone in prostate, liver, and skin

PURPOSE: Benign prostatic hyperplasia (BPH), androgenic alopecia

ADVERSE: Neoplasm of male breast, breast tenderness, decreased libido, erectile dysfunction, ejaculatory disorder

CONTRA: Known or suspected pregnancy, women and children

NOTES: Finasteride improves symptoms of decreased urine flow; Finasteride is a potential alternative to transurethral resection of the prostate (TURP); One year of therapy can result in up to 25% reduction of prostate - most effective for patients w/large prostates

*Women should not handle finasteride tablets

Front 220

221. What are the aromatase inhibitors and how do they work?

Back 220

1. Anastrozole
2. Letrozole
3. Exemestane
4. Formestane

B/c estrogens are synthesized from androgen precursors via aromatase, blocking aromatase can effectively inhibit estrogen formation.

This approach is used to inhibit the growth of estrogen-dependent tumors such as breast cancer.

Front 221

221. Anastrozole, Letrozole, Exemestane, Formestane

Back 221

MOA: Anastrozole and Letrozole are competitive inhibitors of aromatase. Exemestane and Formestane are irreversible (covalent) inhibitors of aromatase.

PURPOSE: Treatment and prevention of estrogen receptor positive early-stage, locally advanced, and metastatic breast cancer

ADVERSE: Osteoporotic fractures, thromboplebitis, hypercholesterolemia, profuse vaginal bleeding; peripheral edema, rash, nausea, arthralgia, bone pain, headache, depression, dyspnea.

CONTRA: Hypersensitivity to these drugs

Front 222

222. NOTES for inhibitors of aromatase

Back 222

1. Aromatase inhibitors are used to treat estrogen dependent tumors.
2. Aromatase inhibitors may be more effective than estrogen receptor antagonists or SERMs for the treatment of breast cancer.
3. Due to the profound suppression of estrogen action, women taking aromatase inhibitors are at substantial risk for osteoporotic fractures..

Front 223

223. What are the names of the SERMs, and how do they work?

Back 223

1. Tamoxifen
2. Clomiphene
3. Raloxifene

Estrogen receptor antagonist in some tissues and estrogen agonist in other tissues.

The basis for tissue selectivity may be related to tissue specific expression of estrogen receptor subtypes and the differential ability of the ligand-receptor complex to recruit transcriptional co-activators and co-repressors.

Front 224

224. Tamoxifen

Back 224

MOA: Estrogen receptor antagonist in breast tissue and a partial agonist in the endometrium and bone.

PURPOSE: Prevention of breast cancer, palliative treatment of metastatic breast cancer, adjuvant therapy of breast cancer after primary excision of the tumors (lumpectomy)

ADVERSE: Malignant neoplasm of endometrium, cerebrovascular accident, cataract, pulmonary embolism; hot flashes, abnormal menstruation, vaginal discharge

CONTRA: History of DVT or pulmonary embolism if used for breast cancer prevention or ductal carcinoma in situ; in patients w/invasive breast cancer, benefits of tamoxifen outweigh risks of recurrent thromboembolic disease, PREGNANCY

NOTES: Associated with a 4-6x increase in incidence of endometrial CA; usually administered for no more than 5 years in order to minimize the risk of iatrogenic endometrial CA.

Front 225

225. Clomiphene

Back 225

MOA: Estrogen receptor antagonist in the hypothalamus and anterior pituitary gland, and a partial agonist in the ovaries. Disinhibits GnRH release, leading to increased levels of LH and FSH; results in ovulation

PURPOSE: Female infertility due to ovulatory disorder.

ADVERSE: Thromboembolism, ovarian cysts, ovarian hypertrophy, flushing, vasomotor symptoms, abdominal discomfort

CONTRA: Pregnancy, uncontrolled thyroid or adrenal dysfunction, liver disease, endometrial carcinoma, ovarian cysts, organic intracranial lesion

NOTES: Unlike exogenous FSH, clomiphene use is rarely associated w/the ovarian hyperstimulation syndrome.

Front 226

226. Raloxifene

Back 226

MOA: Estrogen receptor agonist activity in bone, but antagonist activity in both breast and endometrial tissue.

PURPOSE: Treatment of osteoporosis in post menopausal women

NOTES: The agonists activity of raloxifene in bone decreases bone resorption, and thus delays or prevents the progression of osteoporosis in postemenopausal women.

Raloxifene does not appear to increase the incidence of endometrial cancer.

Front 227

227. What is the name of the only estrogen receptor antagonist, and how does it work?

Back 227

Fulvestrant competitively inhibits estrogen binding to receptor, blocking the action of estrogen on target tissues.

It is a pure estrogen receptor antagonist with no agonist activity; it binds with high affinity to estrogen receptor, preventing receptor dimerization and increasing receptor degradation.

Sometimes referred to as the first in a new class of selective estrogen receptor down-regulators (SERDs)

Front 228

228. Fulvestrant

Back 228

MOA: Competitively inhibits estrogen binding to receptor, blocking the action of estrogen on target tissues

PURPOSE: Treatment of estrogen receptor positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy

ADVERSE: Nausea, asthenia, pain, vasodilation (hot flashes), headache

CONTRA: Pregnancy

Front 229

229. What are the names of the androgen receptor antagonists, and how do they work?

Back 229

Flutamide and spironolactone

Androgen receptor antagonists competitively inhibit the binding of endogenous androgens to the androgen receptor. By this mechanism, receptor antagonists block the action of testosterone and dihydrotestosterone on their target tissues.

Front 230

230. Flutamide

Back 230

MOA: Competitively inhibit testosterone and dihydrotestosterone binding to receptor, blocking the action of testosterone and dihydrotestosterone on target tissues

PURPOSE: Metastatic prostate cancer, and BPH

ADVERSE: Hepatotoxicity, disorders of the hematopoietic system, hot flash, diarrhea, nausea, rash

CONTRA: Severe hepatic impairment

NOTES: Flutamide compares favorably to DES and leuprolide monotherapy in the treatment of prostate cancer. Flutamide is most effective when combined w/medical or surgical castration.

Front 231

231. Sprironolactone

Back 231

MOA: (Aldosterone antagonist) Competitively inhibit testosterone and dihydrotestosterone binding to receptor, blocking the action of testosterone and dihydrotestosterone on target tissues

PURPOSE: Hirsutism, acne vulgaris, hypertension, edema associated w/heart failure, cirrhosis (w/or w/o ascites), or nephrotic syndrome, hypokalemia, primary aldosteronism

ADVERSE: Hyeprkalemic metabolic acidosis, GI hemorrhage, agranulocytosis, SLE, breast cancer, gynocomastia, dyspepsia, lethargy, abnormal menstruation, impotence, rash

CONTRA: Anuria, hyperkalemia, acute renal insufficiency

NOTE: An aldosterone receptor antagonist that also has significant antagonist activity at the androgen receptor.

Front 232

232. What is drospirenone?

Back 232

Drospirenone is a compound derived from spironolactone that has both progestational and anti-androgen effects.

It is used as a progestin in some estrogen-progestin contraceptives.

Front 233

233. What are the names of the two progesterone receptor antagonists?

Back 233

Mifepristone (RU-486) and asoprisnil

Front 234

234. Mifepristone (RU-486)

Back 234

MOA: Inhibits progesterone action by binding competitively to the progesterone receptor. Blockade of progesterone action results in decay and death of the decidua, and lack of decidua causes the blastocyst to die and detach from the uterus.

PURPOSE: Abortion (through day 49 of pregnancy)

ADVERSE: Prolonged bleeding time, bacterial infections, sepsis, nausea, vomiting, diarrhea, cramps, abnormal vaginal bleeding, headache

CONTRA: Chronic adrenal failure, ectopic pregnancy, hemorrhagic disorders, antigcoagulation therapy, inherited porphyrias, intrauterine device, undiagnosed adnexal mass.

Front 235

235. Therapeutic considerations for mifepristone (RU-486)

Back 235

Mifepristone is commonly administered in conjunction with misoprostol, a prostaglandin analogue that stimulates uterine contractions; coadministration of misoprostol can cause nausea and vomiting.

At higher concentrations, mifepristone also blocks the glucocorticoid receptor, which makes it potentially useful for treating conditions associated w/life-threatening elevated glucocorticoid levels, such as the ectopic ACTH syndrome.

Front 236

236. Asoprisnil

Back 236

MOA: Novel progesterone receptor antagonists that inhibits the growth of tissues derived from the endometrium and myometrium

PURPOSE: Investigational agent for the treatment of endometriosis and uterine leiomyomata (fibroids)

Front 237

237. What are the names of the estrogens in combination estrogen-progestin contraception?

Back 237

1. Ethinyl estradiol
2. Mestranol

Front 238

238. What are the names of the progestins in combination estrogen-progestin contraception?

Back 238

1. Norgestrel
2. Levonorgestrel
3. Norethindrone
4. Norethindrone acetate
5. Ethynodiol
6. Gestodene
7. Desogestrel
8. Drospirenone
9. Norgestimate

Front 239

239. MOA Combination estrogen-progestin contraception

Back 239

MOA: Suppress GnRH, LH, and FSH secretion and follicular development, thereby inhibiting ovulation; secondary mechanism of pregnancy prevention include alterations in tubal peristalsis, endometrial receptivity, and cervical mucus secretions, which together prevent the proper transport of both egg and sperm.

Front 240

240. ADVERSE and CONTRA for combination estrogen-progestin contraception

Back 240

ADVERSE: Arterial and venous thromboembolism, pulmonary embolism, cerebral thrombosis, gallbladder disease, hypertension, hepatic neoplasm; abnormal menstruation, breakthrough bleeding, breast tenderness, bloating, migraine, weight change

CONTRA: Breast CA, endometrial CA or other estrogen dependent neoplasms, cerebral vascular or coronary artery disease, cholestatic jaundice of pregnancy or jaundice with prior hormonal contraceptive use, benign or malignant liver tumors, severe hypertension, prolonged immobilization, pregnancy, female smokers > 35 y/o, thrombotic disorders

Front 241

241. Therapeutic considerations for combination estrogen-progestin contraception

Back 241

1. B/c unopposed estrogen increases the risk of endometrial CA, estrogen is always coadministered with a progestin in women with a uterus.
2. Progestins vary in the androgenic activity
3. Combination estrogen-progestin contraceptives are available in oral tablets, a vaginal ring, and transdermal patches.
4. Biphasic or triphasic oral formulations have lower total amounts of progestin each month
5. The lowest effective dose of ethinyl estradiol is preferred to reduce the risk of DVT.

Front 242

242. What are the relative potencies of androgenic activities of the progestins?

Back 242

Norgestrel and levonorgestrel have the highest androgenic activity.

Norethindrone and norethindrone acetate have medium androgenic activity.

Ethynodiol, norgestimate, gestodene and desogestrel have low androgen receptor cross-reactivity.

Drospirenone is a synthetic progestin that also has anti-androgenic activity

Front 243

243. What is another use for levonorgestrel?

Back 243

Levonorgestrel is also used for emergency (morning after) contraception.

Front 244

244. What is in the vaginal ring contraceptive?

Back 244

The vaginal ring consists of a silastic cylinder packed with ethiny estradiol and etonogestrel.

The steroids are released with zero-order kinetics. The ring is placed in the vagina and remains there for 21 days. It is then removed and 7 days later, a new ring is placed.

Front 245

245. What is in the transdermal patch contraceptive?

Back 245

The contraceptive transdermal patch consists of a matrix that continually releases ethinyl estradiol and norelgestromin.

The patch is changed weekly for 3 weeks. During the fourth week, no patch is utilized and menses may occur.

Front 246

246. What is the most common phasic preparation of contraceptives?

Back 246

Most women have a constant (monophasic) dose of estrogen and progestin for 21 days.

Front 247

247. What are the features of biphasic preparations?

Back 247

Biphasic preparations maintain a constant estrogen dose throughout the cycle, while the progestin is initially low but then increases during the second half of the cycle.

Front 248

248. What are the features of triphasic preparations?

Back 248

Triphasic formulations incorporate both increased progestin in the latter half of the cycle and a mid-cycle increase in the estrogen dose, to prevent breakthrough bleeding.

Front 249

249. What is the main advantage of biphasic or triphasic administration of contraceptives?

Back 249

The main advantage is that the total amount of progestin administered over each month is reduced.

Front 250

250. What does gallbladder disease have to do with oral contraceptives?

Back 250

Use of oral contraceptives is associated w/an increase in gallbladder disease, b/c estrogen increase the biliary concentration of cholesterol relative to that of bile salts, and the resulting decrease in cholesterol solubility promotes the formation of gallstones.

Front 251

251. What are the progesterone only contraceptives?

Back 251

1. Norgestrel
2. Norethindrone
3. Medroxyprogesterone acetate (injectable)
4. Etonogestrel (silastic implant)

Front 252

252. Progesterone only contraceptives

Norgestrel
2. Norethindrone
3. Medroxyprogesterone acetate (injectable)
4. Etonogestrel (silastic implant)

Back 252

MOA: Alter frequency of GnRH pulsing and decrease anterior pituitary gland responsiveness to GnRH. Secondary mechanism of pregnancy prevention include alterations in tubal peristalsis, endometrial receptivity, and cervical mucus secretions, which together prevent the proper transport of both egg and sperm.

PURPOSE: Contraception

ADVERSE: Irregular periods, breast tenderness, nausea, dizziness, headache.

CONTRA: Acute liver disease, benign or malignant liver tumors, known or suspected breast CA, pregnancy

NOTES: Breakthrough spotting and irregular, light menstrual periods commonly occur during the first year of administration; medroxyprogesterone acetate can be given parenterally every 3 months; a silastic implant that releasts etonogestrel is effective for 3 years.

Front 253

252. What are the names of the two male contraceptives?

How do they work?

Back 253

1. Parental testosterone enanthate plus daily oral levonorgestrel
2. Parental testosterone undecanoate plus injectable medroxyprogesterone acetate

Studies indicate that administration of both an androgen and a progestin is superior to an androgen alone in suppressing spermatogenesis, b/c the combination more completely suppreses gonadotropin release.

Adverse effects are acne, weight gain, polycythemia, and a potential increase in prostate size.

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253. What are the names of the androgens used for hormone replacement?

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Testosterone enanthate and testosterone cypionate

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254. Testosterone enanthate and cypionate

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MOA: Replacement of testosterone to produce androgenic effects, including growth and maturation of the prostate, seminal vesicles, penis, and scrotum, development of male hair distribution, laryngeal enlargement, vocal cord thickening and alterations in body musculature and fat distribution.

PURPOSE: Hypogonadism

ADVERSE: Cholestatic jaundice syndrome, liver carcinoma, benign prostatic hyperplasia, prostate CA; acne, gynocomastia, oral irritation with buccal delivery, skin irritation with transdermal delivery, potential transfer to female partner with topical gel formulation, headache

CONTRA: Breast CA in men, prostate CA, pregnancy when used in women.

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255. Therapeutic considerations for androgen hormone replacements

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1. Various delivery routes have been developed; testosterone replacement can be administered intramuscularly, transdermally, and via topical gel formulation. The transdermal delivery system ahs the advantages that plasma testosterone levels remain relatively constant and first-pass hepatic metabolism is bypassed. Testosterone can also be administered as a tablet that adheres to the buccal mucosa.

2. Androgen replacement therapy should only be offered to men with consistent symptoms and signs of hypogonadism and low plasma testosterone levels (< 3.0 ng/ml); testosterone should not be administered to men with prostate CA.

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256. What are the differences in treatment for estrogen and progestin replacement therapy in women with a uterus vs. those without a uterus?

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W/uterus, estrogen therapy must be combined with progestin therapy to prevent the induction of endometrial CA.

W/o a uterus, estrogen alone is typically give for hormone therapy.

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257. What are some potential benefits/risks of estrogen hormone replacement therapy?

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Estrogen treatment did not increase the risk of coronary heart disease or breast CA, but it did increase the risk of stroke and thromboembolism and it decreased the risk of osteoporotic fracture.

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258. What are some potential benefits/risks of continuous estrogen-progestin hormone replacement therapy?

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Continuous estrogen-progestin treatment increased the risk of cardiovascular events, breast CA, and stroke, and it decreased the risk of osteoporotic fracture.