10/16- Case Conference 4: Reproduction

Question 1

Case 1

HISTORY:

• RG is a 22-year-old automobile mechanic who presents with breast enlargement. He first noted some breast enlargement around the age of 15. It has not been painful but it has gotten more apparent over the years. He no longer goes swimming or wears T-shirts because of his embarrassment.
• He relates that he began to develop sexually around the age of 14, and he never has used street drugs or other medications.
• He currently has a girlfriend and is sexually active
• He is taller than other members of his family.
• He completed high school, but he had to work hard to make “C’s

PHYSICAL EXAM:

• VS: Height 74 inches; u/l 34/40; span 76 inches; weight 185; BP 120/84; pulse 72; temperature 98.8
• General: He is a well-developed, eunuchoid-appearing, young white male.
• Skin and Hair: The skin is pigmented in exposed areas. Hair patterns reveal some recession of the temporal hairline, normal axillary hair, a male escutcheon, a light beard, and light body and extremity hair.
• Lymph nodes: No pathological enlargement of lymph nodes is noted.
• Neck: The thyroid is normal. No masses are noted and carotid pulses are normal.
• Chest: The chest is symmetrical. Breasts are enlarged, measuring 7 cm on the contour. No tenderness or discharge is noted.
• Abdomen: The abdomen is slightly protuberant. Bowel sounds are normal. No masses or organomegaly are noted.
• Genitalia: The penis is normal in size. The testes measure 1.0 x 0.5 cm and are moderately firm. The epididymes are palpable.
• Back and Extremities: He has no deformities and no limitation of motion.
• Rectal Examination: Sphincter tone is good. The prostate is palpable and somewhat smaller than normal for a person his age. No masses are noted. Stool is negative for blood.
• Nervous System: Affect is somewhat flat. Cranial nerves are intact. No neurological abnormalities are noted.

LABS:

• CBC: hematocrit: 39%
• Chemistries: normal
• Testosterone: 350 ng/dL (300-1000 ng/dL); LH 15 mIU/mL (2-12 mIU/mL), FSH: 40 mIU/mL (1-8 mIU/mL)

What is the hormonal mediator of breast enlargement?

Significant features and their meaning?​

Answer 1

Breast enlargement mediated by:

• Estrogens; consider testosterone:estrogen ratio in males (decrease in this ratio will present with gynecomastia)
• Either low testosterone or increased estrogen

Significant features/meaning:

• Normal U:L body ratio ~ 1 (in infants, way > 1); estrogen normally mediates epyphyseal fusion and stopping bone growth?
• Somewhat late start to puberty
• Physical exam implies hormonally interrupted puberty; if hypogonadism occurred after puberty, he wouldn’t have these height changes (would have hair changes and whatnot, but body structure would be normal)
• Light beard and male pattern of body hair and at least some testicular development indicates taht there is at least some amount of testosterone (some degree of androgen activity; although may be insufficient)
• Psychological effects: flat affect and poor student

Question 2

LABS:

• CBC: hematocrit: 39%
• Chemistries: normal
• Testosterone: 350 ng/dL (300-1000 ng/dL); LH 15 mIU/mL (2-12 mIU/mL), FSH: 40 mIU/mL (1-8 mIU/mL)

What is the significance of his lab values?

Describe forms of testosterone found in the blood.

Answer 2

• Testosterone is in the normal range but low (young men have higher levels of testosterone than old; declines with age); so this is definitely concerning
• Gonadotropin (LH, FSH) levels will tell you what the pituitary is thinking about your testosterone levels. Here, you have high LH and FSH, indicating that axis (hypothalamus and pituitary) is functioning but testosterone levels are not responsding; primary testicular failure

Side note on testosterone values/bioavailability:

• Testosterone is in the blood in three main fractions:
• Free (1-4%)
• Sex hormone binding globulin (~60%)
• Bound to albumin (~40%)
• Only free and albumin bound T are bioactive!
• If you have high SHBG, then total testosterone may seem normal/high, but may be biodefficient

Question 3

Case 1 cont’d)

What additional tests would you like to order to make a diagnosis (for what is causing his primary testicular failure)?

Answer 3

Other labs already pointed toward primary testicular failure (Low T despite high gonadotropins)

History is pointing towards Klinefelter’s (47 XXY)

• Psychosocial and cognitive impairments
• Testicular failure

Diagnose with karotype

• Could also look at prolactin levels (although not necessary, because pituitary seems fine)
• Semen analysis would show very very low sperm count (chance of fertility with Klinefelter’s is pretty proprotional to testicular size)

Question 4

How would you treat this patient? (with primary testicular failure, psychosocial issues, and gynecomastia due to Klinefelter’s)

Answer 4

• Testosterone
• May improve testosterone:estrogen ratio to prevent progression of gynecomastia…. but exogenous testosterone may be estrogenized and sometimes contributes independently to gynecomastia
• Some studies to treat hypogonadism with DHE (since it can’t be estrogenized)
• Testosterone decreases axis function; fewer gonadotropins (esp FSH?) means smaller testicular size!! Not larger. Testosterone actually used as contraceptive in men
• Breast reduction surgery for gynecomastia
• Can even get testicular implants

Question 5

Case 2)

• A 27-year-old married female presents with oligomenorrhea
• She had menarche at age 10 and her periods were occasionally irregular but she was able to conceive and had her first child at age 24

What is on your DDx to explain her primary complaint?

Answer 5

DDx: oligomenorrhea

• Secondary amenorrhea
• Recent exercise changes, anorexia, or high stress job
• Pituitary level
• Pituitary adenoma (nonfunctional)
• Cushing’s
• Any acquired pituitary deficits
• Hypothyroidism

Irregular periods early on in life suggests a process that began way earlier in life…

DDx: anovulation in adult women:

• PCOS?

Question 6

• A 27-year-old married female presents with oligomenorrhea.
• She had menarche at age 10 and her periods were occasionally irregular but she was able to conceive and had her first child at age 24.
• ​On further history, she has steadily gained weight since her pregnancy and now she weighs 240 pounds and is 5’ 3” with a waist circumference of 92 cm.
• She says her periods occur every three to four months and lasting six to seven days with heavy bleeding.
• She has noticed increased dark chin and upper lip hair, which she treats with waxing or shaving.
• The PE reveals a generalized obesity. Her BP is 150/90. She has mild hirsutism on her chin, upper lip and peri-aeriolar regions and acanthosis at the back of her neck.
• She has evidence of acne scars on her face and back. Her breasts are large without nodules or discharge.
• The pelvic exam is normal but it is difficult to palpate the adnexal areas and define the uterus because of her obesity.

What test do you order first?

What are the criteria for PCOS?

Other things on DDx?

What is LH:FSH ratio in PCOS?

Answer 6

• First: order pregnancy test! (hers is negative)

Polycystic ovary syndrome (need 2/3):

• Ultrasound of cysts
• Clinical or biochemical hyperandrogenism: she has hirsuitism
• Oligomenorrhea

Must also rule out other possibilities:

• Malignancy producing androgen axis
• ACTH dependent Cushing’s (stimulating reticularis and adrenal galnd stimulation)
• Congenital adrenal hyperplasia

Other things that can disrupt period:

• Hyperthyroidism
• Pelvic ultrasound
• Check LH and FSH levels
• Hyperprolactinemia (may work up… but should NOT present with hyperandrogenism)

Commonly have high LH:FSH ratio in lean PCOS (not diagnostic, but commonly seen)

Question 7

Case 2 cont’d)

• ​Recent labs from her primary care physician reveal a fasting glucose of 100 mg/dl and elevated fasting triglycerides (250 mg/dL).
• Her fasting total cholesterol and LDL cholesterol levels are normal, but her HDL cholesterol is low (30 mg/dL).

What are the long term health risks associated with this syndrome?

Answer 7

Diabetes complications

• Vascular morbidity/mortality (micro and macro)
• Retinal, nephropathy…

Endometrial cancer (not sloughing uterine lining)

Question 8

Case 2 cont’d)

What treatments can you offer her (PCOS)?

• She would like to conceive again

Answer 8

• Diet and exercise

If wanting to get pregnant:

• Metformin: reduce insulin resistance and improve cycling (although not that effective for re-esta
• Clomiphine citrate: blocks estrogen receptors on hypothalamus to remove negative feedback and upregulate
• Ovarian diathermy: decrease ovarian androgen excess to get more successful cycling later? (efficacy unclear)
• Thiazolidinedione: again to help with insulin resistance

If not wanting to get pregnant:

• Oral contraception (reduces endometrial cancer risk….and pregnancy)

Question 9

How to diagnose Cushing’s?

• Intense… discuss

Answer 9

First most important step is to establish cotisolemia!!

3 options to establish cortisolemia (should get 2/3):

1. 24 hour urine collection
2. Midnight salivary cortisol (normally values are very low; in Cushing’s, you lose normal diurnal variation)
3. Low dose dex suppression test
   - Dexamethasone is a glucocorticoid. Expected (normal) effect would be to suppress the pituitary and cause a resultant drop in cortisol

After establishment of hypercortisolemia, would start localizing