PHYSIOLOGY OF FEMALE REPRODUCTION

- Normal function of the menstrual cycle requires careful coordination of

INHIBITION and STIMULATION between the hormonal axis:
o Hypothalamic: GnRH
o Pituitary: FSH, LH
o Ovarian: estradiol and progesterone
- GnRH pulse frequency varies in the menstrual cycle to promote follicular
development and ovulation
- The FSH level increases slightly in the early follicular phase of menstrual
cycle which begins with the onset of menstrual bleeding (day 1)
o The increase leads to  recruitment of ovarian follicles 
increase in estradiol (stimulates endometrial proliferation) and
induction of LH receptors in the ovaries
- Estradiol creates a positive feedback on the pituitary gland and makes LH
surge  high LH results in ovulation and initiates the luteal phase of
menstrual cycle
o LH also stimulates theca cell androgen production
o Androgens are aromatized to estrogen in granulosa cells by FSH
- After the LH surge, the corpues luteum secretes ESTRADIOL + PROGESTERONE
o Declining progesterone lead to menstrual bleeding unless conception has occurred
- Average normal menstrual cycle: 28-35 days in length
- Luteal phase: 14 days
- Follicular phase: 14-21 days
- More cycle length variation occurs in the first 5 years of menstruation and a decrease in follicular phase length
occurs during perimenopause
- Menstrual cycles <25 days and more than 35 days are likely anovulatory

Primary Amenorrhea
- Lack of menstruation by age 16 accompanied by normal body hair pattern and normal breast development
- Pregnancy must be ruled out
- 50%  chromosome abnormality:
o gonadal dysgenesis
- 15%  anatomic abnormality of the uterus, vagina, or cervix
- One of the most common causes: Tuner Syndrome:
o Short stature
o Loss of all X chromosome
o Amenorrhea
o Ovarian insufficiency
o Dx  karyotype
- Dx turner syndrome critical  affected patients have cardiovascular disease, metabolic syndrome, thyroid
dysfunction

Secondary Amenorrhea
- The absence of a menstrual cycle for three cycles or 6 months in previously menstruating women
- Pregnancy is the most common cause
- Uterine or outflow tract disorder (Asherman syndrome) must be considered
- Asherman syndrome:
o Due to endometrial scarring after uterine procedure
o Should be considered in women with amenorrhea and past exposure to uterine instrumentation
- After pregnancy is excluded  40% of secondary amenorrhea will be due to ovarian causes such as
polycystic ovarian syndrome (PCOS)
- Additional causes:
o Hypothalamic functional amenorrhea  18-40 years (dx of exclusion)
 RF:
 Low body weight and fat percentage
 Eating disorders
 Excessive exercise
 Severe emotional stress
  Nutritional deficits
 FSH and LH really low, but FSH is higher than LH
o Hyperprolactinemia
 Because it inhibits GnRH secretion
o Thyroid disease (hypo and hyper)
 Hypothyroidism  increased levels of TRH which stimulates prolactin secretion 
inhibits GnRH  inhibits ovulation
 Hyperthyroidism  fast weight loss
o Primary ovarian insufficiency
 Amenorrhea before 40 y.o with two elevated FSH levels
 Secondary causes: turner, fragile X permutation status, autoimmune oophoritis, effects of
quimio and radiotherapy

Diagnosis and Evaluation of Amenorrhea

- Initial evaluation: history + exam +:
o HCG levels  d/c pregnancy
o Prolactin levels  d/c hyperprolactinemia
o FSH levels  d/c Primary ovarian insufficiency
o TSH levels  d/c thyroid disease
- A pelvic ultrasound is required in primary amenorrhea
- A pituitary MRI is required in these patients if primary ovarian insufficiency is excluded as a cause and in
patients with secondary amenorrhea that is hypothalamic in nature
- If prolactin level is high  evaluate for causes of hyperprolactinemia
o Patients meds
o Thyroid status
o Kidney function
o Imaging of pituitary gland to evaluate for pituitary adenoma
- If FSH is made in 2 different occasions  DX OF PRIMARY OVARIAN INSUFFICIENCY IS MADE
o Patients with these findings should get a karyotype to evaluate for Turner and should be tested for
fragile X mutation
- If tests are normal 
o Next step: assess estrogen sufficiency with a progesterone challenge test
 It will delineate between estrogen-deficient (no bleeding) state or estrogen sufficient
state (bleed)
 If a patient is producing estrogen  she will have withdrawal bleeding in 1 week of
completing a course of progesterone
- If patient is not estrogen deficient  PCOS should be considered
- If no withdrawal bleeding happens  patient has a low estrogen state  dx: hypothalamic amenorrhea
- If no clear cause of hypothalamic amenorrhea is present, then a pituitary MRI should be ordered to rule out
pituitary adenoma

HIRSUTISM AND POLYCYSTIC OVARY SYNDROME

- Hirsutism: excess in terminal hair growth in women in androgen-dependent areas of the body
o The patients familiar hair pattern should be taken into account when assessing for hirsutism
o When its present  patient should be evaluated for virilization which is commonly due to ovarian
or adrenal tumor
o Signs and symptoms of virilization:
 Deepening of voice
 Severe acne
 Clitoromegaly
 Decrease in breast size
 Male pattern balding
 Rapid onset hirsutism (in 1 year) or hirsutism that develop after 30 (concerning features)
o Recommended exams:
 Plasma DHEA sulfate level
 If >700 micrograms/mL  adrenal CT is necessary to exclude an adrenal cortisol-
secreting and or androgen secreting neoplasm
 TSH
 Prolactin
  Total testosterone
 If >200 ng/dL: Pelvic ultrasound and adrenal CT necessary to exclude ovarian or
adrenal neoplasm
 Follicular phase 17-hiydroxiprogesterone
 To exclude:
 Thyroid disease
 Hyperprolactinemia
 Ovarian and adrenal tumors
 Late onset congenital adrenal hyperplasia
o Most causes of hirsutism are benign such as PCOS
- PCOS:
o Oligomenorrhea and clinical or biochemical evidence of hyperandrogenism
o 2 of the following must be present to diagnose PCOS:
 1. Oligo-ovulation or anovulation
 2. Clinical or biochemical evidence of hyperandrogenism
 3. Polycystic ovarian morphology on an ultrasound when other endocrine disorders
are excluded
o Clinical manifestations:
 Menstrual irregularity (oligo or amenorrhea)
 Ovulatory dysfunction  infertility
 Insulin resistance
 Hyperandrogenism
o Improvement in insulin resistance with weight loss or use of metformin is associated with a decrease
in serum androgen levels  also improved ovulatory rates with increased pregnancy rates
o Treatment:
 Weight loss and exercise
 Hyperandrogenism  oral contraceptives
 Spironolactone  may be added after 6 months if acne and hirsutism are still cosmetically
bothering the patient
 Hirsutism  waxing, electrolysis, laser therapy
 Menstrual irregularities  contraceptives, provide endometrial protection
 Insulin resistance  metformin, diet and exercise
o If patient has contraindication to oral contraceptives or does not wish to take them cyclical
progesterone can be given to induce withdrawal bleeding

ANABOLIC STEROID ABUSE IN WOMEN

- Enhance their athlete performance or physique (that’s what they use them for)
- Adverse effects:
o Hirsutism
o Acne
o Deepening of the voice
o Decreased breast size
o Clitoromegaly
- Withdrawal of androgen  severe hypogonadism

FEMALE INFERTILITY
- Infertility: inability to conceive in 1 year with regular unprotected sexual intercourse
- If female partner is older than 35 years then infertility is defined as the inability to conceive within 6 months
- Exams:
o TSH
o Prolactin
- If initial testings are normal  referral to reproductive endocrinologist is indicated
o Evaluation will continue with semen analysis of the partnet
o Confirmation of ovulatory function with mid-luteal progesterone level measurement
o Ovarian reserve testing by measuring FSH level on day 3 of menstrual cycle
o Hysterosalpingography 6-10 days in menstrual cycle to evaluate for any uterine or tubal
abnormalities
- If there is no abnormalities 
o Clomiphene
o Gonadotropins