From our anonymous insider…
“This is for 3,000 years of patriarchy!” exclaimed a female classmate as she slices off the penis. Today we are dissecting the external genitalia. We noted the three main regions of the penis: left corpus cavernosum, right corpus cavernosum, and corpus spongiosum.
Lectures introduced the female reproductive cycle, also known as the hypothalamus-pituitary-ovarian (HPO) axis.
This topic requires us to learn the derivatives of cholesterol and the enzymes that catalyze these conversions (graphic). Cholesterol is a 27-carbon structure that gives rise to numerous signaling molecules such as androgens, estrogens, progesterone, aldosterone (isoosmotic antidiuretic) and cortisol. When discussing cholesterol signaling, there are two questions: What enzymes are found in what cell? How much access does the given cell have to low-density lipoproteins (LDL) in circulation?
Two-thirds of the class is memorizing the names and important enzymes in First-Aid that will be tested on Step I. For example, they memorize 17-alpha hydroxylase deficiency will lead to increased aldosterone and cortisol levels with decreased sex hormones and ambiguous genitalia. They aren’t trying to learn the structure of cholesterol. I am wishing them good luck in retaining that information for next year.
The cells of the body have an ability to make fine distinctions among these related cholesterol-derived compounds. For example, aldosterone is very similar in structure to glucocorticoids (e.g., cortisol). So similar that kidney cells’ aldosterone receptors have an affinity to cortisol. However, the aldosterone receptor is typically near an enzyme that degrades cortisol into cortisone which has a lower affinity. In this clever way, the aldosterone receptor can maintain its high sensitivity (percent true positive) to aldosterone while increasing the specificity (percent true negative). [After you enjoy a bag of licorice, it is possible to have transient psuedohyperaldosteronism, including hypertension and hypokalemia from cortisol activating the aldosterone receptor; licorice inhibits the activity of the enzyme that degrades cortisol into cortisone.]
The menstrual cycle is divided into the ovarian cycle (follicular and luteal phase) and the uterine cycle (proliferative and secretory phase). Different regions in the hypothalamus release pulses of Gonadotropin-Releasing Hormone (GnRH) into the pituitary portal system. GnRH activates gonadotroph cells in the pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH) into the systemic circulation. FSH and LH act on ovarian follicles.
Each follicle is surrounded by granulosa cells that nurture a single dormant egg. Outside the granulosa cells are connective tissue called theca cells. LH binding to theca cell receptors initiates a signaling cascade that increases cholesterol uptake into the cell and increases transcription of the enzymes required to convert cholesterol into androgens. These androgens diffuse out of the cell and suppress further development of the follicle.
FSH binding to granulosa cell receptors upregulate aromatase, the enzyme that converts androgens into estrogens. Granulosa cells do not have the enzymes to synthesize androgens (estrogen precursor) themselves. Follicles are selfish. Once FSH has selected a follicle it will suppress other follicles from maturing, thereby ensuring only one follicle ovulates each cycle.
As FSH increases aromatase activity in granulosa cells, estrogen levels rise throughout the follicular phase of the ovary. Estrogen has many effects including proliferation of the uterine lining (proliferative phase of the uterus). Estrogen also has negative feedback on the neurons in the hypothalamus controlling GnRH release and negative feedback on the gonadotropins in the pituitary. Every 26-32 days in a healthy female, estrogen levels reach such high levels that the negative feedback switches to positive feedback. (The mechanism of this about-face remains a mystery to medicine.) The positive feedback produces the LH surge, a massive release of LH and FSH from the pituitary, initiating ovulation.
Ovulation is the rupture of the follicle. The oocyte or egg is released into the peritoneal cavity (space between abdominal wall and visceral gut organs) where the fimbriae of the fallopian tube sweeps it into the fallopian tube. Fertilization typically occurs in the ampulla of the fallopian tube and is carried into the uterus for implantation. An ectopic pregnancy occurs when a fertilized egg implants anywhere outside the uterus, most commonly in the fallopian tube. However, our embryology professor mentioned it is possible to have implantation in the peritoneal cavity on the the connective tissue of the gut.
After ovulation, the follicle enters the luteal phase. The ruptured follicle becomes the corpus luteum, a highly vascularized endocrine structure. Before, only the theca cells had adequate access to cholesterol in the bloodstream. Now, the granulosa cells have abundant access to cholesterol from LDL in the blood. Granulosa cells lack the enzyme to convert cholesterol into androgens. They are able only to convert androgens into estrogens and cholesterol into an androgen precursor, progesterone. Thus, progesterone levels spike initiating the secretory phase of the uterus. The uterus is ready for implantation of a fertilized egg. If fertilization occurs, the placenta secretes HCG (a close analog of LH) which preserves the corpus luteum production of progesterone. If fertilization does not occur, the corpus luteum involutes (degrades) causing progesterone withdrawal. This sudden decrease in progesterone causes shedding of the uterine lining or menstruation. The decline in progesterone and estrogen disinhibits the GnRH pulsations initiating the whole cycle again.
Two-thirds of the males had at best a fuzzy knowledge of the menstrual cycle. For example, how long is it? When do menses takes place in relation to ovulation? About half of the women did not know how their birth control works. Classmates argued about whether males should be given a handicap for the reproductive block: “You females have it easy. We’ve never seen this stuff before.”
Our patient case: Gina, 31-year-old overweight female presenting with amenorrhea (lack of periods) and hirsutism (hair growth on chin, armpits, etc.). A pregnancy test is negative. A hormone panel reveals high levels of estrogens, androgens and LH.
Gina suffers from Polycystic Ovarian Syndrome (PCOS). PCOS is named for the ultrasound appearance of small cysts in the ovary. Confusingly these fluid-filled sacs are not “ovarian cysts,” but simply mature follicles that are unable to ovulate. The elevated levels of androgens inhibit further maturation of follicles and ovulation and cause hair growth. The endocrinologist explained that hair growth, especially on the chin and neck, is what brings women to her office: “The amenorrhea is alarming but it is not what typically brings them in.”
PCOS affects about eight percent of reproductive age females, although there is not a standardized diagnostic criteria for PCOS and the causes are not fully understood. Diabetes and obesity are known risk factors: adipose (fat) tissue produces androgens, which interfere with follicle maturation. The inability to menstruate is serious. The uterus is stuck in proliferation mode, which vastly increases the risk of endometrial (lining of the uterus that regenerates every cycle) cancer.
How do we get Gina to ovulate? The endocrinologist explained how every woman’s HPO axis is different. “It’s really trial and error.” Gina, like many women with suspected PCOS or infertility issues, undergo a progesterone challenge. A high dose progesterone injection is given initiating the transition from the proliferative phase of the uterus (high estrogen, low progesterone) to the secretory phase of the uterus (high progesterone). Once progesterone is metabolised, progesterone withdrawal should initiate menses. This confirms that the problem is an inability to ovulate.
Gina is taking clomiphene, a drug also used to treat infertility. Clomiphene inhibits estrogen receptors in the hypothalamus to prevent estrogen negative feedback. Therefore, there continues to be release of GnRH and downstream release of FSH despite the presence of estrogen at levels which should cause negative-feedback . Clomiphene increases the risk of twins as multiple ovulations may occur. Gina also underwent what sounds like a barbaric procedure called ovarian drilling. A needle inserted laparoscopically destroys various follicles in a random array. Ovarian drilling is quite successful in decreasing androgen levels and inducing ovulation. Gina still is not on a normal cycle, but has been menstruating. She is trying to get pregnant with her husband.
[See also “Small-sample Behavioral Economics” for how clomiphene may be taken by women with normal fertility.]
Statistics for the week… Study: 20 hours. Sleep: 7 hours/night; Fun: 1 night. Example fun: One of our classmates recently moved in with two males in their 20s. Her new apartment is a bachelor pad equipped with a pool table, beer pong table, dart board and xbox. After two weeks of straight exam study, she was demonstrating her social skills by hosting a 26th birthday party for another classmate.
> adipose (fat) tissue produces androgens
Fat produces estrogens, not androgens. PCOS is associated with high estrogen and prolactin levels and low progesterone levels.
Creepy woman.