Differentials

Common

Eating disorders or female athlete triad

History

weight loss, anorexia, altered bowel habits, sleep disturbances, dry skin, competitive sports

Exam

low BMI (10% less than ideal body weight), normal secondary sexual characteristics, normal external and internal genitalia

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    low to normal

    More
  • serum estradiol:

    low

    More
  • serum thyroid-stimulating hormone:

    normal

  • serum prolactin:

    normal

  • pelvic ultrasound:

    thin endometrial echo-complex

    More
Other investigations
  • serum LH:

    low

    More
  • dual energy x-ray absorptiometry scan:

    low bone density

    More
  • progestin challenge test:

    variable withdrawal bleed

    More

Emotional or physical stress

History

weight loss, anorexia, sleep disturbances, dry skin, prescription drugs

Exam

low BMI (10% less than ideal body weight), normal secondary sexual characteristics, normal external and internal genitalia

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    low to normal

    More
  • serum estradiol:

    low

    More
  • serum thyroid-stimulating hormone:

    normal

  • serum prolactin:

    normal

  • pelvic ultrasound:

    thin endometrial echo-complex

    More
Other investigations
  • serum LH:

    low

    More
  • dual energy x-ray absorptiometry scan:

    low bone density

    More
  • progestin challenge test:

    variable withdrawal bleed

    More

Postcontraception with depot medroxyprogesterone

History

history of depot medroxyprogesterone

Exam

normal secondary sexual characteristics, normal external and internal genitalia

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    low to normal

    More
  • serum estradiol:

    low

    More
  • serum thyroid-stimulating hormone:

    normal

  • serum prolactin:

    normal

  • pelvic ultrasound:

    thin endometrial echo-complex

    More
Other investigations
  • serum LH:

    low

    More
  • dual energy x-ray absorptiometry scan:

    low bone density

    More
  • progestin challenge test:

    variable withdrawal bleed

    More

Hyperprolactinemia

History

galactorrhea (some patients), headache or visual disturbances (prolactinoma); may present with oligomenorrhea if prolactin levels are not extremely elevated

Exam

visual field deficit (some patients)

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum prolactin:

    elevated; >100 nanograms/mL is highly suggestive of prolactinoma

    More
  • serum follicle-stimulating hormone (FSH):

    low to normal

    More
  • serum estradiol:

    low

    More
  • serum thyroid-stimulating hormone:

    usually normal

    More
  • MRI brain:

    possible pituitary tumor

  • pelvic ultrasound:

    thin to variable endometrial echo-complex

    More
Other investigations
  • serum LH:

    low to normal

    More
  • progestin challenge test:

    variable withdrawal bleed

    More

Polycystic ovary syndrome (PCOS)

History

slowly progressive symptoms, deepening of voice, male-pattern hair growth or loss, oily skin, weight gain, oligoanovulatory cycles to amenorrhea (if peripubertal onset, may present with delayed menarche), history of premature pubarche, depression

Exam

androgenic alopecia, acanthosis nigricans, increased waist-hip ratio, clitoromegaly, acne, hirsutism, obesity (BMI >30)

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    normal

    More
  • serum estradiol:

    normal to elevated

    More
  • serum thyroid-stimulating hormone:

    normal

  • serum prolactin:

    normal

  • serum dehydroepiandrosterone sulfate:

    elevated

  • total serum testosterone:

    elevated; marked elevation suggests ovarian/adrenal tumor

    More
  • free serum testosterone:

    elevated

    More
  • serum 17-hydroxyprogesterone (17-OHP):

    normal fasting levels help rule out 21-hydroxylase deficiency

    More
  • 2-hour oral glucose challenge:

    elevated insulin levels

    More
  • fasting serum lipid profile:

    elevated triglycerides and LDL

    More
  • pelvic ultrasound:

    polycystic ovaries; variable endometrial echo-complex

Other investigations
  • serum LH:

    elevated (LH:FSH ratio >2:1)

    More
  • progestin challenge test:

    positive withdrawal bleed

    More

Idiopathic premature ovarian failure

History

age <40 years, vasomotor symptoms, vaginal dryness, decreased libido, fatigue, weight gain

Exam

postpubertal external genitalia, adult secondary sexual characteristics

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    elevated (>25 units/L)

    More
  • serum estradiol:

    low to undetectable

    More
  • serum thyroid-stimulating hormone:

    normal

  • serum prolactin:

    normal

  • pelvic ultrasound:

    thin endometrial echo-complex

    More
Other investigations
  • serum LH:

    elevated

    More
  • serum inhibin:

    low

    More
  • karyotype (if age <30 years):

    may suggest gonadal dysgenesis

    More
  • progestin challenge test:

    no withdrawal bleed

Postchemoradiation ovarian failure

History

vasomotor symptoms, vaginal dryness, decreased libido, fatigue, weight gain

Exam

normal adult secondary sexual characteristics

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    elevated (>25 units/L)

    More
  • serum estradiol:

    low to undetectable

    More
  • serum thyroid-stimulating hormone:

    normal

  • serum prolactin:

    normal

  • pelvic ultrasound:

    thin endometrial echo-complex

    More
Other investigations
  • serum LH:

    elevated

    More
  • progestin challenge test:

    no withdrawal bleed

Chromosomal abnormality (Fragile X carrier, Turner syndrome mosaic)

History

age <40 years, vasomotor symptoms, vaginal dryness, decreased libido, fatigue, weight gain; may lack hypoestrogenic complaints but stop cycling

Exam

Turner mosaic: fewer physical manifestations as compared with full syndrome; may have isolated oligoamenorrhea; Fragile X carrier: may have large ears

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    elevated (>25 units/L)

    More
  • serum estradiol:

    low to undetectable

    More
  • serum thyroid-stimulating hormone:

    normal

  • serum prolactin:

    normal

  • pelvic ultrasound:

    thin to variable endometrial echo-complex

    More
Other investigations
  • serum LH:

    elevated

    More
  • serum inhibin:

    low

    More
  • karyotype (if age <30 years):

    may suggest gonadal dysgenesis

    More
  • progestin challenge test:

    no withdrawal bleed

Nonclassic congenital adrenal hyperplasia

History

presents in late childhood to early adult life; obesity, hirsutism, acne, weight gain, history of premature pubarche

Exam

androgenic alopecia

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    normal

    More
  • serum estradiol:

    normal to elevated

    More
  • serum thyroid-stimulating hormone:

    normal

  • serum prolactin:

    normal

  • serum dehydroepiandrosterone sulfate:

    elevated

  • total serum testosterone:

    elevated; marked elevation suggests ovarian/adrenal tumor

    More
  • serum 17-hydroxyprogesterone (17-OHP):

    elevated fasting levels (>200 nanograms/dL)

    More
  • pelvic ultrasound:

    variable endometrial echo-complex

Other investigations
  • serum LH:

    normal

    More
  • free serum testosterone:

    elevated

    More
  • progestin challenge test:

    positive withdrawal bleed

    More

Hypothyroidism

History

oligomenorrhea more common than amenorrhea; lethargy, dry skin, constipation, weight gain, paresthesias, cold intolerance, galactorrhea

Exam

low resting heart rate, periorbital puffiness, delayed ankle deep tendon reflexes, cold and coarse skin

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum thyroid-stimulating hormone (TSH):

    high in primary hypothyroidism

    More
  • serum follicle-stimulating hormone (FSH):

    normal

    More
  • serum prolactin:

    normal to high

    More
  • serum estradiol:

    low to normal

    More
  • pelvic ultrasound:

    variable endometrial echo-complex

Other investigations
  • serum LH:

    normal

    More
  • serum free thyroxine (T4):

    low

    More
  • progestin challenge test:

    variable withdrawal bleed

Uncommon

Malnutrition or chronic disease state

History

history of chronic disorder (e.g., celiac disease), weight loss, anorexia

Exam

low BMI (10% less than ideal body weight), normal secondary sexual characteristics, normal external and internal genitalia

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    low to normal

    More
  • serum estradiol:

    low

    More
  • serum thyroid-stimulating hormone:

    normal

  • serum prolactin:

    normal

  • pelvic ultrasound:

    thin endometrial echo-complex

    More
Other investigations
  • serum LH:

    low

    More
  • dual energy x-ray absorptiometry scan:

    low bone density

    More
  • progestin challenge test:

    variable withdrawal bleed

    More

Empty sella syndrome

History

mass in sella turcica or previous central nervous system surgery/radiation/infarction; headache, galactorrhea, or visual disturbances may be seen with associated prolactinoma

Exam

visual field deficit (some patients)

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    low to normal

    More
  • serum estradiol:

    low

    More
  • serum thyroid-stimulating hormone:

    low to normal

  • serum prolactin:

    normal; >100 nanograms/mL highly suggestive of prolactinoma

  • MRI brain:

    pituitary lesion or empty sella

  • pelvic ultrasound:

    thin to variable endometrial echo-complex

    More
Other investigations
  • serum LH:

    low to normal

    More
  • progestin challenge test:

    variable withdrawal bleed

    More

Sheehan syndrome (postpartum pituitary necrosis)

History

severe obstetric hemorrhage, hypotension, and shock with postpartum panhypopituitarism (after volume and blood resuscitation), nausea, vomiting, lethargy, failure to breastfeed, slowed mental function, fatigue, weight loss, delayed symptoms of hypothyroidism

Exam

postural hypotension, loss of axillary and pubic hair, adrenal crisis (with skin depigmentation), rapidly involuting breasts, periorbital edema

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    low

    More
  • serum estradiol:

    low

    More
  • serum thyroid-stimulating hormone:

    low

    More
  • serum free thyroxine (T4):

    low

    More
  • serum prolactin:

    normal

  • serum growth hormone:

    low

  • serum adrenocorticotropic hormone:

    low to normal

    More
  • serum sodium:

    may be low

    More
  • morning serum cortisol:

    may be low

    More
  • MRI brain:

    sella empty or cerebrospinal fluid-filled; potentially small pituitary gland

    More
  • pelvic ultrasound:

    thin to variable endometrial echo-complex

    More
Other investigations
  • serum LH:

    low

    More
  • adrenocorticotropic hormone stimulation test:

    lack of cortisol response

    More
  • progestin challenge test:

    no withdrawal bleed

Postencephalitis

History

previous infectious process, headache, altered vision

Exam

visual field defects, normal phenotypic female

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    low

    More
  • serum estradiol:

    low

    More
  • serum thyroid-stimulating hormone:

    normal

  • serum prolactin:

    normal

  • MRI brain:

    cerebral atrophy

  • pelvic ultrasound:

    thin to variable endometrial echo-complex

    More
Other investigations
  • serum LH:

    low

    More
  • progestin challenge test:

    variable withdrawal bleed

    More

Androgen-producing ovarian tumor

History

rapidly progressive symptoms, obesity, hirsutism, acne, deepening voice, male-pattern hair growth or loss, oily skin, weight gain, oligoanovulatory cycles to amenorrhea

Exam

androgenic alopecia, clitoromegaly, male-pattern hair growth, increased muscle mass

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    normal

    More
  • serum estradiol:

    normal to elevated

    More
  • serum thyroid-stimulating hormone:

    normal

  • serum prolactin:

    normal

  • serum 17-hydroxyprogesterone (17-OHP):

    normal fasting levels help rule out 21-hydroxylase deficiency

    More
  • serum dehydroepiandrosterone sulfate (DHEAS):

    normal

  • total serum testosterone:

    elevated (>200 nanograms/dL)

    More
  • pelvic ultrasound:

    ovarian mass; variable endometrial echo-complex

Other investigations
  • serum LH:

    normal

    More
  • free serum testosterone:

    elevated

    More
  • MRI abdomen and pelvis:

    ovarian mass

    More
  • progestin challenge test:

    positive withdrawal bleed

    More

Autoimmune premature ovarian failure

History

age <40 years, vasomotor symptoms, vaginal dryness, decreased libido, fatigue, weight gain

Exam

normal adult secondary sexual characteristics

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    elevated (>25 units/L)

    More
  • serum estradiol:

    low to undetectable

    More
  • serum thyroid-stimulating hormone:

    usually normal; associated autoimmunity may cause hypothyroidism (more common) or thyrotoxicosis

  • serum prolactin:

    usually normal, unless secondary elevation due to hypothyroidism

  • serum free thyroxine (T4):

    usually normal; associated autoimmunity may cause hypothyroidism (more common) or thyrotoxicosis

  • serum thyroid antibodies:

    may be present

    More
  • morning serum cortisol:

    may be low if Addison disease present

  • serum calcium:

    may be low if autoimmune hypoparathyroidism present

  • serum phosphorus:

    may be elevated if autoimmune hypoparathyroidism present

  • fasting serum glucose:

    may be elevated if type 1 diabetes mellitus present

  • pelvic ultrasound:

    thin endometrial echo-complex

    More
Other investigations
  • serum LH:

    elevated

    More
  • 24-hour urine calcium:

    may be low if autoimmune hypoparathyroidism present

  • serum adrenal antibodies:

    may be positive

    More
  • serum inhibin:

    low

    More
  • karyotype (if age <30 years):

    may suggest alternate diagnosis of gonadal dysgenesis

    More
  • serum corticotropin stimulation test:

    may show lack of cortisol response if Addison disease present

    More
  • progestin challenge test:

    no withdrawal bleed

Androgen-producing adrenal tumor

History

rapidly progressive symptoms, obesity, hirsutism, acne, deepening voice, male-pattern hair growth or loss, oily skin, weight gain, oligoanovulatory cycles to amenorrhea

Exam

androgenic alopecia, clitoromegaly, male-pattern hair growth, increased muscle mass

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    normal

    More
  • serum estradiol:

    normal to elevated

    More
  • serum thyroid-stimulating hormone:

    normal

  • serum prolactin:

    normal

  • serum 17-hydroxyprogesterone (17-OHP):

    normal fasting levels help rule out 21-hydroxylase deficiency

    More
  • serum dehydroepiandrosterone sulfate:

    markedly elevated

  • total serum testosterone:

    elevated (>200 nanograms/dL)

    More
  • pelvic ultrasound:

    variable endometrial echo-complex

Other investigations
  • serum LH:

    normal

    More
  • free serum testosterone:

    elevated

    More
  • MRI abdomen and pelvis:

    adrenal mass

  • progestin challenge test:

    positive withdrawal bleed

    More

Cushing syndrome

History

bruisability, poor healing, weakness, weight gain, hirsutism, diabetes mellitus, hypertension, galactorrhea (some patients), headache or visual disturbances (pituitary adenoma), may present with oligomenorrhea

Exam

central obesity with thin extremities, nuchal fat pad, moon facies, purple striae

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    normal

    More
  • serum estradiol:

    normal to elevated

    More
  • serum thyroid-stimulating hormone:

    normal

  • serum prolactin:

    normal

  • 24-hour urinary free cortisol:

    elevated

  • morning serum cortisol:

    elevated

  • serum adrenocorticotropic hormone (ACTH):

    elevated if Cushing disease (pituitary) or ectopic source

  • pelvic ultrasound:

    variable endometrial echo-complex

Other investigations
  • serum LH:

    normal

    More
  • high- and low-dose dexamethasone suppression test:

    lack of cortisol suppression

    More
  • late-night salivary cortisol:

    elevated

    More
  • MRI brain:

    possible pituitary adenoma

    More
  • progestin challenge test:

    variable withdrawal bleed

Asherman syndrome

History

amenorrhea following an intrauterine procedure (dilatation and curettage for second-trimester abortion or pregnancy loss, or complication of postprocedural endometritis, myomectomy, cesarean delivery), moliminal symptoms (these are a useful clinical indicator of a normal reproductive cycle; they include increase in midcycle thin cervical secretions, and premenstrual symptoms such as menstrual cramps, breast tenderness, fluid retention, and mood or appetite changes)

Exam

normal adult secondary sexual characteristics and external genitalia

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    normal

    More
  • serum estradiol:

    normal

    More
  • serum thyroid-stimulating hormone:

    normal

  • serum prolactin:

    normal

  • hysterosalpingogram:

    irregular, scattered contour of contrast within the endometrial cavity, possible lack of contrast within oviducts due to obliterative process

    More
  • pelvic ultrasound:

    thin to variable endometrial echo-complex

    More
Other investigations
  • serum LH:

    normal

    More
  • diagnostic hysteroscopy:

    obliterated endometrial cavity (variable)

  • progestin challenge test:

    variable withdrawal bleed

Drug-induced

History

history of use of birth control pills (however, these should not cause secondary amenorrhea, as most users have return of function within 2 months of discontinuing), long-acting progestins, androgens, antipsychotics (may down-regulate hypothalamic-pituitary-ovarian axis by way of dopaminergic pathways), or chronic cocaine or opioid use[19]

Exam

usually normal; some psychotropics may cause galactorrhea

1st investigation
  • serum human chorionic gonadotropin:

    negative

  • serum follicle-stimulating hormone (FSH):

    low to normal

    More
  • serum estradiol:

    low

    More
  • serum thyroid-stimulating hormone:

    normal

  • serum prolactin:

    normal to elevated

  • pelvic ultrasound:

    thin endometrial echo-complex

    More
  • serum LH:

    low

    More
Other investigations
  • dual energy x-ray absorptiometry scan:

    low bone density

    More
  • progestin challenge test:

    variable withdrawal bleed

  • Urine drug screen:

    may be positive

    More

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