Causes of amenorrhea
How can Cushing disease lead to amenorrhea?
- ACTH excess causes hyperstimulation of the zona fasciculata and zona reticularis and results in hypersecretion of cortisol and androgens - The mechanism of anovoluation is also unclear, but potentially due to glucocorticoid suppression of the HPG axis (decreased GNRH) and hyperandrogenemia
SUMMARY
- Consider congenital abnormalities in a patient with primary amenorrhea. - Anatomical abnormalities and disruption of the hypothalamic/pituitary/ovarian axis are common causes of both primary and secondary amenorrhea, and require a careful history, physical exam, and diagnostic workup.
What is the female athlete triad?
1. Amenorrhea 2. Disordered eating 3. Osteoporosis/osteopenia
Anatomical cases of amenorrhea
1. Congenital vaginal anomalies = primary amenorrhea - *Transverse septum:* improper fusion of mullerian ducts and urogenital sinus - *Atresia/agenesis:* failure of urogenital sinus to normally develop - *Imperforate hymen* or transverse septum: can present with cyclical or acute pelvic pain - *Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome* - *Androgen insensitivity syndrome (AIS)* - *5-alpha reductase deficiency* 2. Uterine/outflow obstruction = Secondary amenorrhea from scarring - *Asherman syndrome:* uterine scarring following procedures such as repeated dilution and curettage (D&C), a procedure to removal tissue from inside the uterus
Multifactorial causes of amenorrhea
1. Contraceptives 2. Chronic disease - Malnutrition: hypothalamic hypogonadism - Hormone metabolism/clearance: Renal/liver dysfunction, increased metabolism 3. Obesity - Dysregulation of metabolic, endocrine, and inflammatory pathways - PCOS 4. PCOS: multiple theories - Genetic - Environmental - Ovarian: androgen overproduction leading to pituitary dysregulation - Pituitary: increase LH pulse and frequency leading to increased androgen production by ovaries - Metabolic syndrome 5. Cushing syndrome 6. Thyroid disorders
Hormonal causes of amenorrhea
1. Hypothalamic - Genetic GnRH deficiency: Kallman syndrome - Infiltration: Sarcoidosis, Langerhans cell histiocytosis, lymphoma - Infection: Meningitis, TB, Syphilis - Traumatic brain injury - Tumor 2. Hypothalamic (functional) Amenorrhea - Reproductive axis suppression due to energy deficit; reduction in central neural drive of GNRH pulse generator (as an adaption to stress) - Causes include: eating disorder, acute or chronic illness, excessive exercise, stress, malabsorption, nutritional deficiency, low BMI, rapid weight loss - Diagnosis of exclusion - Eg female athlete triad: amenorrhea, disordered eating, osteoporosis/osteopenia 3. Pituitary - Autoimmune: example lymphocytic hypophysitis: inflammation of the pituitary of unknown cause which lead to infiltration by lymphocytes with enlargement or destruction of the pituitary, generally occurring in late pregnancy or the postpartum period - Infiltrative disease: sarcoidosis, hemochromatosis - Tumor (in pituitary) - Sheehan syndrome: hypopituitarism due to ischemic necrosis during childbirth (in setting of blood loss) - Hyperprolactinemia
How can thyroid disorders lead to amenorrhea?
1. Hypothyroidism - ↑ TRH = ↑ prolactin - Altered estrogen metabolism - Decreased SHBG = increased free androgens 2. Hyperthyroidism - Weight loss leading to hypothalamic amenorrhea - Premature ovarian failure
Chromosomal causes of amenorrhea
1. Idiopathic hypogonadotropic hypogonadism - Kallman syndrome 2. Ovarian apoptosis - Turner syndrome
How can metabolic syndrome lead to PCOS?
1. Insulin resistance in tissues leads to hyperglycemia and increased insulin production 2. Hyperinsulinemia suppresses SHBG production in liver (increasing levels of free serum androgens), increases steroid storage in fat tissues, and increases LH release from the pituitary (increasing signaling for ovarian androgen production) 3. Increased aromatization of androgen to estrogen in peripheral tissues.
What do the following structures become embryologically: 1. Mullein (paramesonephric) duct 2. Mesonephric (Wollfian) duct 3. Urogenital sinus
1. Mullein (paramesonephric) duct - Uterus, fallopian tubes, upper 1/3 vagina 2. Mesonephric (Wollfian) duct - Normally regresses in females 3. Urogenital sinus - Lower 2/3 vagina, urethra
Categories of causes of amenorrhea
1. Physiologic 2. Chromosomal 3. Anatomical 4. Hormonal 5. Multifactorial
Ovarian causes of amenorrhea
1. Primary ovarian insufficiency - <40 2. Genetics - Turners, fragile X 3. FSH, LH receptor 4. Autoimmune - Graves' disease, thyroiditis, hypoadrenalism, diabetes, hypoparathyroidism, myasthenia gravis, polyendocrinopathies, alopecia, vitiligo, rheumatoid arthritis, systemic lupus erythematosus, lymphocytic oophoritis 5. Infection - STIs, mumps, CMV 6. Tumor - Androgen producing 7. Chemotherapy 8. Radiation 9. Infiltration
A 16 year old woman without significant past medical history is evaluated for amenorrhea. She has never had a period. She denies sexual activity and takes no medications. Family history is remarkable for hypothyroidism. On physical examination vitals signs are normal; BMI is 22 (height 58 in, weight 107 lbs). Visual field, thyroid, and pelvic examinations are normal. Results of laboratory studies show an initial serum FSH of 53 mU/mL and subsequent level of 62 mU/mL on repeat testing (both high). TSH, hCG, and prolactin are normal. Which karyotype would you expect in this patient? - 46XY - 46XX - 45X - 47XXY
45X (Turner syndrome) - Short stature, elevated FSH (indicates primary ovarian insufficiency), primary amenorrhea - Further testing is necessary
Turner syndrome
45X karyotype - Ovarian tissue replaced with fibrous tissue - Normal external genitalia/uterus - Short stature, facial, skin, MSK anomalies - Generally patients with Turners do not have menses due to lack of ovarian hormone release, but patients with mosaic karyotype can have menstruation
What is amenorrhea?
Absence of menses
A 25 year old woman presents with a 3 year history of increasing hair growth on the upper lip, chin, and sides of the face. She underwent menarche at age 12 years and has had irregular menses since that time. Her last period was 4 months ago. Vitals: BMI is 27 Thyroid exam is normal. Mild acanthosis nigricans of the axillae and neck and terminal hair growth on the chin, upper lip, and sides of the face are noted. No evidence of abdominal or pelvic masses, clitoromegaly, or galactorrhea is detected. Labs: - Normal fasting glucose, DHEA, FSH, 17-hydroxyprogesterone, prolactin, and TSH - Mildly elevated total testosterone Diagnosis? - Ovarian tumor - Adrenal tumor - PCOS - CAH
All can cause secondary amenorrhea with normal FSH and hirsutism PCOS - PCOS: Mild elevation in estrogens (testosterone or DHT) - Ovarian tumor: Total testosterone > 200 ng/dl likely ovarian neoplasm - Adrenal tumor: DHEA > 7 likely adrenal origin - CAH :(21-hydroxylase deficiency): would expect elevated 17-OH progesterone
MRKH vs AIS
Both primary amenorrhea and absence of uterus
Kallman syndrome
Congenital GnRH deficiency - Delayed/incomplete puberty - Multiple gene defects (>20) identified - Rare - Midline facial defects (include anosmia)
A 13-year-old female presents for pelvic pain which occurs for several days every month. She has never had a period and denies sexual activity. Examination reveals Tanner stage 4 breasts and Tanner stage 3 pubic hair. Abdominal exam reveals a suprapubic mass that is fluctuant and moderately tender without rebound or guarding. Her pelvic exam is notable for a bulging bluish membrane across the vaginal vestibule. Diagnosis?
Imperforate hymen - Physical abnormality at level of suprapubic area - Transverse vaginal septum can have a similar clinical presentation, on exam would find blockage of outflow tract more proximally in the vagina
Hyperprolactinemia
Increased level of prolactin in the serum Causes: 1. Medications: suppress dopamine which increases prolactin - Anti-nausea: Metoclopramide - Psychiatric: Anti-psychotics, MAO-I, Tricyclics, SSRIs - Antihypertensives: verapamil, methyldoxpa - Other: thorazine, reserpine, cocaine 2. Infiltration 3. Tumor 4. Radiation of pituitary 5. Pregnancy 6. Lactation 7. Stress 8. Seizure 9. Renal disease 10. Liver disease
A 17 year old female presents with no menses for the past six months. She underwent menarche at age 14, and previously had irregular bleeding. She is sexually active with a male partner and uses condoms. She reports a 10 pound weight loss in the past year and is a competitive cross country runner. She denies headache, vision changes, depression, anxiety, galactorrhea, abdominal pain, or hot flushes. Vitals: Height 5'5", weight 110 lbs (BMI 18.3) Exam: tanner 5 breasts/pubic hair, patent vagina Ultrasound: normal uterus and ovaries Labs - TSH normal - Prolactin normal - HCG negative Which of the following lab results would you expect in this patient? - Low FSH, high estradiol - Low FSH, low estradiol - High FSH, high estradiol - High FSH, low estradiol
Low FSH, low estradiol - Patient has history consistent with hypothalamic hypogonadism
5 alpha reductase deficiency
Mutations in the SRD5A2 gene - Cannot convert testosterone to dihydrotestosterone (more powerful metabolite) which leads to lack of normal enlargement of male external genitalia - Autosomal recessive; sex limited to genetic males (46,XY) - Ambiguous/female genitalia until puberty, when ↑ testosterone causes masculinization & ↑ growth of external genitalia (virilization during puberty) - Testosterone/estrogen levels are normal; LH is normal or ↑ - Internal genitalia are normal.
Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome
Müllerian agenesis - May present with primary amenorrhea in females with fully developed secondary sex characteristics - Absence of uterus: failure of the caudal development of the Müllerian ducts - Upper vagina/uterus/cervix anomalies - Ovaries = normal - Several genes identified but cause unknown
Physiologic causes of amenorrhea
Normal functioning of the body - Pregnancy - Breastfeeding - Menopause
What is the most common cause of secondary amenorrhea?
Pregnancy
Primary vs secondary amenorrhea
Primary: - Absence of menarche by age 15 years - Age 13 without secondary sex ual characteristics Secondary: - Absence of menses for more than three months (3 cycles) in girls or women who previously had regular menstrual cycles or six months in girls or women who had irregular menses
Androgen insensitivity syndrome (AIS)
Resistance of androgen receptor to stimulation from testosterone - Result = patient with female external genitalia with blind vaginal pouch - Form of primary amenorrhea - Signal from testosterone does not reach the wollfian ducts and instead of being signaled to develop into male internal genitalia (seminal vesicles, epididymis, ejaculatory duct, ductus deferens), they regress - Similarly, lack of perceived androgen signal from dihydro-testosterone to the urogenital sinus and genital tubercule leads to lack of development of the male external genitalia and prostate