W3006 Physiology Fall 2002 Problem set #4 - Male & female reproduction and sexual differentiation
1. In a rabbit fetus with XX genotype, you implant a testis next to the ovary, only on the right side, before the ducts have developed. What kind of ducts would you expect to develop on both sides?
2. To ensure that only women compete in women's sports, some games required that participants have a genetic test to prove they are women; XX individuals could participate, XY individuals couldn't. You make the following argument: Rather than dismissing those individuals with "male chromosomes", they should dismiss only those individuals whose male‑like musculature gives them an unfair advantage over women. To support your argument, describe two types of XY individuals who should be allowed to compete, because they lack masculine muscles. For each type, name the disorder they have, and describe the appearance of the gonad, Wolffian duct, Mullerian duct, external genitals, and the major gonadal hormone produced.
3. Gonads were removed from fetal sheep and grown in organ culture, either in control medium, or in medium containing AMH (Anti‑ Mullerian Hormone = MIH). After a few days, the researchers measured the amount of testosterone and estradiol produced, as well as the amount of aromatase activity. (Aromatase is the enzyme that converts T to E. Results are graphed here. These results suggest that (besides the role we discussed in class) there is another role for AMH in sexual development. What is that role? How do these results lead to that conclusion?
4. Describe two natural conditions during which a woman might get a false positive response on a home pregnancy test. (that is, it says she's pregnant but she's really not.)
5. The ancient Greeks produced statues of Hermaphrodite, a god with male genitals, but female breasts and musculature.
A. These statues suggest that the ancient Greeks were familiar with;
a. congenital adrenal hyperplasia b. androgen insensitivity syndrome c. guevodoces d. XX with SRY
B. For each of these four anomalies, describe the type of breast development and genital development expected in the adult: (male or female) a. CAH b. AIS c. Guevodoces d. XX with SRY
6. Vinclozolin is used to kill fungi that may grow on certain fruits and vegetables. Since Vinclozolin is rapidly degraded, it has not considered harmful to humans. However, recent studies show that Vinclozolin is degraded to two compounds, M1 and M2, and that these may be toxic. To study the basis of this toxicity, M1 and M2 were administered to pregnant rats. When their pups were born, some of the males were found to have a phallus that was incompletely fused (that is, with a small vaginal-like opening). However, their testosterone levels were similar to those of untreated controls.
Suggest two molecular processes that might have been inhibited by the fungicide. Explain how inhibition of either of these steps would lead to this partial de-masculinization of the male genitals.
7. The year is 2005. You've just opened a medical practice and the federal government and all the insurance companies have just gone bankrupt. A woman enters your office, wanting to know whether she is ovulating during her menstrual cycles, though she is not concerned about pinpointing the exact time of ovulation. (In some cycles there is no ovulation, but as estrogen levels gradually fall, menstruation occurs anyway.) You have enough money to perform just one assay for just one hormone just one time. Which hormone do you choose (estrogen, progesterone, GnRH, LH, or FSH)? Why this hormone and not each of the others? How will you calculate the day to take a blood sample to measure it?
8. Spotted hyena males and females are difficult to tell apart. The female has an extremely large clitoris that resembles a penis, and fused labia that look like a scrotum. Which one of these is most likely to explain this masculinization of the female genitals? Explain your answer.
A. Females produce high levels of cortisol, which has the usual negative feedback effects.
B. The mother's ovaries produces androstenedione, a steroid which can be converted into other androgens.
C. Females lack a Y chromosome, but have the sex-determining region of the Y chromosome which has crossed over to their X chromosome.
D. Females produce mullerian-inhibiting hormone in their ovaries.
E. The enzyme responsible for converting testosterone to dihydrotestosterone is not functional in the females.
F. Females lack androgen receptors.
9. A man is found to have elevated plasma FSH, normal LH, normal T, and atrophied seminiferous tubules. Explain what the probable defect is.
10. Some people take anabolic steroids, drugs that act like androgens to increase muscle mass. These drugs are similar to androgens in other ways, too, which helps us to understand why they can cause certain side effects. Explain the mechanism by which anabolic steroids cause these two side effects:
A. testicular atrophy (testes get smaller)
B. gynecomastia (breasts enlarge)
11. Cells slough off the walls of the vagina and can easily be removed and examined under the microscope (like you may have looked at cheek cells under the microscope in lab class). As the estrous cycle progresses, different types of cells become prominent, as diagrammed below for the 4 day estrous cycle. Considering these changes, and considering the concomitant changes in estrogen, devise a method of using the female rat for a bioassay for estrogen.
12. Scientists wanted to know how hormones are involved in the occurrence of menstruation during an anovulatory cycle (i.e., no ovulation occurs). They did the following experiment on a group of female rhesus monkeys who had had their ovaries removed One or two Silastic implants containing hormone are put under the skin of each monkey. Two weeks later, one implant was removed from each animal, and the animals were observed for 2 days to see whether menstruation occurred.
Expt Implant(s) After 2 wks, remove implant containing menstruation?
1 E E yes
2 P P yes
3 one E, one P E no
4 one E, one P P yes
What hormonal change is responsible for menstruation in an anovulatory cycle? From where does the hormone come? Explain. Your answer should include an explanation of why each of the four experiments were necessary to reach this conclusion.
13. Indicate whether a>b, a=b, or a<b
A. a. plasma concentration of progesterone during the follicular phase of the menstrual cycle
b. plasma concentration of progesterone during the luteal phase of the menstrual cycle
B. a. length of the luteal phase of the menstrual cycyle
b. length of the secretory phase of the menstrual cycle
C. a. frequency at which eggs are fertilized in the uterus
b. frequency at which eggs are fertilized in the oviduct
14. The presence of _______determines whether the embryonic gonad will differentiate into a testis.
a. the X chromosome b. the Y chromosome c. testosterone d. DHT (dihydrotestosterone) e. estrogen
f. AMH (Anti-Mullerian Hormone) g. none of the above
15. The Mullerian duct is able to develop into
a. an oviduct, but not a vas deferens b. a vas deferens, but not an oviduct
c. either an oviduct or a vas deferens, depending on which steroid hormone is present
16. The hormone that stimulates ovulation also stimulates
a. spermatogenesis b.testosterone secretion c. development of the corpus luteum d. development of uterine glands
17. The muscle layer of the uterus is called the _____________________________.
18. FSH secretion is inhibited by secretion of _______________________ from Sertoli cells.
19. ___________________________________ are local hormones, derived from fatty acids, that have a variety of effects, including stimulating smooth muscle contraction and raising the hypothalamic set point for temperature.
20. sometimes/ always/ never:
A. An individual with a vas deferens must be a male.
B. The estrogen which is found in blood comes from ovarian follicles.
21. When cancer develops in the prostate gland, it often grows so slowly that it isn't harmful. It can grow more rapidly, however, when gonadal hormones are high. One technique for treating prostate cancer is to give a continual infusion of GnRH. Explain the normal hormones involved, and how this treatment might prevent further prostate growth.
22. What will be the effect of hypophysectomy on the structure of the uterus? Explain why, including in your answer the hormones normally involved.
23. A woman comes to the doctor, thinking she might be pregnant, since her expected menstrual period didn't occur. The doctor palpates her ovary, and feels small bumps on the surface. This suggests that she has follicular cysts, which are follicles that develop just to the point of ovulation, but then stay attached to the ovary without releasing the ova. Explain how these persistent follicles might prevent subsequent menstrual periods.
24. When Mark McGwire established his home-run record, there was much talk about his use of "Andro", technically known as androstenedione, or ASD, one of the androgens naturally produced by the testes. The Endocrine Society put out a press release describing how taking too much Andro can "shrink your grapes to raisins". Why might ASD be able to cause the testes to become smaller? Your answer should include an explanation of how testes size is normally maintained, and where ASD might be having an effect.
1. Right side: Exposed to T and MIH, so Wolffian duct develops into vas deferens and Mullerian disintegrates. Left side: Exposed to T (via blood) but not MIH (because paracrine secretion), so Wolffian duct develops into vas deferens AND Mullerian duct develops into oviducts/uterus.
2. A. Androgen insensitivity syndrome: testis, Mullerian and Wolffian ducts both disintegrate, female genitals, produce T.
B. Lack of SRY region of Y chromosome: ovary, Wolffian disintegrates, Mullerian develops into oviduct/uterus, female genitals, produce E/P.
3. Aromatase converts T to E, so should be more prevalent in ovaries than in testes, and ovaries should produce more estrogen and less testosterone than testes (and this is supported by the results in the graph). The middle bar of each graph shows what happens when ovaries are treated with AMH: They start to act like testes, secreting lots of T, little E, and apparently having this effect because they inhibit activity of the aromatase. Remember, an indifferent gonad can become either an ovary (with aromatase) or a testes (without aromatase), depending on the presence of SRY. Scientists have suggested that SRY might make the gonad male-like by switching off the aromatase gene. The results support the idea that AMH functions to ensure that the testes develops in the male direction, becoming a testosterone-secreting gland, rather than the default estrogen-secreting gland.
4. The home preg test measures hCG, which normally has the effect of maintaining the corpus luteum, just like LH does. In fact, its structure is very similar to that of LH. High LH can react with the antibodies used in the preg test, so she'll give a positive response if she has high LH. This can occur naturally just before ovulation, of course. In addition, it will occur when negative feedback from the ovaries is removed. This occurs naturally at menopause, when the decreased secretion of ovarian hormones leads to high levels of gonadotropic hormones being measured in the blood.
5. A. CAH seems most likely here, since genitals are male-like, and breasts do develop at puberty in response to E. But, in fact, the statues themselves have genitals that are unambiguously male. It could be that they were based on something like CAH, but the traits were exaggerated, or that they were based on Klinefelter's syndrome, in which female-like breasts often develop. It is also, of course, possible that they resulted from the Greeks' imagination, and we'd be mistaken to assume that such people existed, just like archaeologists 2000 years hence would be mistaken to
view objects from our times as evidence that our generation coexisted with a species of purple dinosaur.
B. CAH: genitals: male-like, breasts: female. AIS: both are female. Guevo and XX w/SRY: male genitals & breasts
6. Vinclozolin may inhibit 5-alpha reductase, the enzyme responsible for conversion of T to DHT, so that external genitals do not get enough stimulation for complete masculine development. Alternatively, vinclozolin may be blocking the receptors for DHT, so that even though the hormone is present, it cannot affect the tissue.
7. Significant progesterone is secreted only from the corpus luteum, not the follicle, so you'd expect to see progesterone only in the second half of the cycle, and only if ovulation has occurred. So you'd want to assay in the middle of the luteal phase, but this is hard to pinpoint, since it depends on cycle length. Best estimate would be to start counting from day 1 of menstruation, and then assay 21-22 days later. If the cycle's exactly 28 days, you'd hit the peak of P secretion. If the cycle is shorter or longer than 28 days, you'd be at the beginning or end of the luteal phase, so would still be likely to find P. NOTE: Measuring LH would also indicate the likelihood that ovulation will occur in this cycle, but because the LH peak is very brief (1 day), you're likely to miss this day, considering the lack of equipment available to you. Same argument holds for FSH and GnRH. The latter is also not a good choice, because levels in the peripheral blood are so low. E is high both before AND after ovulation, so if you measure just one point, you won't know which time you're measuring, and whether ovulation occurred.
8. B. Androgens are required for masculinization of external genitals, which usually depends on conversion of testosterone to DHT. In this case, the female produces androstenedione, which crosses the placenta to the fetus. Since it can be converted to other androgens, it's able to masculinize the genitals of the female. (The female actually gives birth through the relatively small vaginal opening in this penis-like organ.)
9. Since LH is normal, the hypothalamus and GnRH must be okay. Problem is either that the Sertoli cells can't respond to FSH (e.g., no receptors), or they don't produce enough inhibin. (In fact, the latter has been shown to occur in some such men.)
10. A. Androgens inhibit GnRh, and gonadotropins, and Gn is needed to maintain testes at normal adult size, so less Gn can lead to smaller testes. B. Androgens can be converted to estrogen, which stimulates breast development. It's possible that the exogenous androgens are converted to E, and/or that they inhibit T production but still allow exogenous T to be converted to E, so the T/E ratio changes in favor of E having a greater effect.
11. Answered in Problem Set #1
12. Expt 2 and 4 show that a sudden lowering of progesterone can bring on menstruation, whether or not estrogen is present. Expt 1 and 3 show that a sudden lowering of E can bring on menstruation, but only if progesterone is absent. In an anovulatory cycle, there is no progesterone since no corpus luteum was formed, and so the menstruation that occurs must be due to the sudden decrease in E secretion, which would come in this case from the follicle, not the corpus luteum.
13. A. b>a B. a=b C. b>a 14. b. (or you could say g. ... requires just SRY) 15. a 16. b. c
17. myometrium 18. inhibin 19. Prostaglandins 20. A. Sometimes. Could be a CAH female.
B. Sometimes. Could be from adrenal cortex, or from peripheral fat cells.
21. Normally: T is converted to DHT, which stimulates prostate development. Normally: Hypothalamus secretes GnRH, stimulating Anterior Pituitary, which secretes LH, to stimulate the Leydig cells of the testes to release Testosterone, which has negative feedback effects on the hypothalamus and anterior pituitary gland. But GnRH is released in pulses, so that the level of LH is also pulsatile. If, instead, level of GnRH is kept constant via continual infusion, then GnRH receptors will down-regulate, making the pituitary less sensitive to GnRH, and LH will decrease, and thereby lead to decreases in T and DHT, so less stimulation of prostate results.
22. Normal hormone pathways are in textbook. Hypophysectomy leads to decreases in LH and FSH, and therefore decreases in E and P. Therefore uterine lining will stay thin, with no secretory glands and no coiled blood vessels.
23. Follicle secretes estrogen, which stimulates endometrial thickening. Normally, follicle ovulates, ovum is released, and follicular cells become corpus luteum, which secretes P and E, having negative feedback effects on LH. After 2 weeks, with the decrease in LH, the CL dies and E and P levels fall. With removal of these hormones, which were maintaining the endometrial lining, the endometrium sloughs off as menses. If no ovulation occurs, the process stops before CL is produced, so there's no E+P to inhibit LH. Instead, LH continues to stimulate follicle, which continues to pour out E, which continues to maintain a thickened uterine lining, i.e., no menstruation.
24. Normally testes size is maintained by gonadotropins; see textbook for flowchart. Testosterone has negative feedback effects on anterior pituitary, causing a decrease in gonadotropins, which would then lead to a decrease in T. So ASD acts like T at the hypothalamus, anterior pituitary, causing a decrease in gonadotropins and a decrease in endogenous T secretion. (It doesn't have strong enough effects on the testes, so effect there is less than the normal T)