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Amenorrhea (Physiologic (Physiology of Bone loss with age: In women, there…

- - - - Presentation: Low FSH, LH and sex hormones (all of the other pituitary hormones are normal). Female external and internal genital organs. Tall with long arms. TS-2-3 breasts, TS-2-3 pubic hair, Decreased sense of smell.
      - Cause: 46,XX phenotypic females. Lack GnRH producing neurons. Low LH and FSH levels. Low ovarian sex hormones. Anosmin controls formation of olfactory tract that direct normal migration of GnRH neurons to the hypothalamus. There is an X-linked recessive LOF mutation of the KAL1 gene -> decreased anosmin -> disrupts olfaction and prevents GnRH neurons into the hypothalamus
  - - - Causes: labial fusion, imperforate hymen, transverse vaginal septum, cervical atresia or stenosis
      - Presentation: 46,XX females with normal external genitalia, breast development, and sexual hair growth. Present with symptoms of cryptomenorrhea (cyclic lower abdominal pain and swelling, difficult urination every 25-35 days)
    - - Mullerian agenesis: 2nd most common cause of primary amenorrhea. 46,XX phenotypic females with normal ovaries. No Fallopian tubes, uterus or proximal vagina. Blind-pouch perineal vaginal opening. Patients will have normal female hormone levels, normal ovulation, normal secondary sexual characteristics.1/3 will have kidney malformations
      - Complete androgen insensitivity syndrome (CAIS) (Testicular feminization syndrome): 46,XY phenotypic females. 1/20,000 live "female" births. XLR-LOF mutation of AR gene. No functioning ARs.
        
        Cause: Presence of SRY gene (Y chromosome) -> fetal testes (undescended). Maternal hCG -> stimulates fetal testes -> T and DHT and Mullerian inhibitory substance (MIS) -> prevents development of female internal duct structures (uterus, Fallopian tubes, upper two-thirds of the vagina). Wolffian duct development and genital virilization never occur because androgen receptors are insensitive to fetal androgens. Thus, fetal development proceeds with normal female external genitalia.
        
        @ puberty: Pubertal surge in LH increases Te synthesis by cryptorchid testes. Te fails to inhibit LH secretion (no ARs). Markedly elevated LH levels raise Te (serum Te higher than normal males). Normal serum FSH and inhibin B levels.
        
        Clinical: No functioning ARs -> tanner stage 1 sexual hair. Excess Te aromatized to estrogen (TS-4 breasts (no PRG), taller than normal females), inguinal testes (5% develop cancer).
  - - - Physical stigmata: shield- like chest, low-set ears, webbed neck, increased carrying angle of the arms, multiple pigmented nevi, renal malformations, and cardiac malformations including bicuspid aortic valve (16-19%) and coarctation of the aorta (13-19%). Also will have short stature (due to deletion of the short stature homeobox-containing gene)
      - Presentation: Girls fail to sexually mature in teenage years. Streak ovaries (streaks of connective tissue that lack ova) -> no gonadal hormones. Elevated FSH and LH. TS-2 breast development, TS-2 pubic hair due to adrenal androgen production.
      - Diagnosis/Treatment: Karyotyping. Treat with combination OCPs (female sexual maturation, early-onset osteoporosis prevention), Growth Hormone to increase weight.
    - - 46,XX gonadal dysgenesis: Gonad- nonfunctioning streak ovaries, Wolffian structures- no epididymis or vas deferens (no Te), Mullerian structures- intact FTs, uterus and vagina (no AMH), Urogenital sinus- perineal vaginal opening (no DHT), Genital tubercle and folds- clitoris and labia (no DHT)
        
        Presentation: Elevated FSH and LH, TS-2 pubic hair and TS-2-3 breast development, Normal female height with long arms, No exam stigmata of Turner syndrome.
      - 46,XY gonadal dysgenesis (Swyer syndrome): Gonad- nonfunctioning streak ovaries, Wolffian structures- no epididymis or vas deferens (no Te), Mullerian structures- intact FTs, uterus and vagina (no AMH), Urogenital sinus- perineal vaginal opening (no DHT), Genital tubercle and folds- clitoris and labia (no DHT)
        
        Presentation: Elevated FSH and LH. TS-2 pubic hair and TS-2-3 breast development. Normal male height with long arm span. No exam stigmata of Turner syndrome
    - - 46,XX (female): Gonad- nonfunctioning ovaries, Wolffian structures- no epididymis or vas deferens (no Te), Mullerian structures- intact FTs, uterus and proximal vagina (no AMH), Urogenital sinus- perineal vaginal opening (no DHT), Genital tubercle and folds- clitoris and labia (no DHT)
      - 46,XY (male): Gonad- cryptorchid testes -> AMH but no androgens, Wolffian structures- no epididymis or vas deferens (no Te), Mullerian structures- no FTs, uterus or vagina (AMH present), Urogenital sinus- blind-pouch perineal vaginal opening (no DHT), Genital tubercle and folds- clitoris and labia (no DHT)
      - Presentation: Patients fail to sexually mature in teenage years. No sex hormones with elevated FSH and LH. TS-1 breast development, TS-1 pubic hair, Tall with long arms.
      - Diagnosis/Treatment: Elevated progesterone and DOC. Treat with Glucocorticoids to resolved HTN and hypokalemia, Estrogen to feminize the patient (domination OCPs for 46,XX), Remove inguinal testes in 46,XY
- - - - Causes
        
        Idiopathic (60%)
        
        X chromosome abnormalities (10%): Partial X deletions, Partial Y deletions.
        
        Familial genetic causes ( 20%): FMR1 gene, INHA gene, EsR and FSHR
        
        Autoimmune conditions (10%): Polyglandular syndrome. Anti-ovarian Abs.
        
        "Other": Cancer chemotherapy or radiation: Differential effects by drugs, dose and age. Alkylating agents are worst offenders in women > 35 years of age. Leuprolide administered during chemo may help preserve ovarian function.
      - Natural History: Normal menarche, normal menses and normal fertility before onset of POI. 10-20% have family history of POI. Patients will present with early onset hot flashes and flushes followed by amenorrhea. 5-10% become pregnant spontaneously.
      - Diagnosis: No early warning signs. Two serum FSH levels > 40 mIU/mL in women younger than age 40. Serum E2 <50 mIu/mL
    - - Presentation: Hyperinsulinemia/IR (in obese patients). Hyperandrogenism -> hirsuitism. Hyperestrogenism (due to ASD being aromatized to estrone in adipose tissue). Estrone concentration is continuously elevated -> abnormal feedback -> increased LH and low FSH. FSH suppressed due to modest elevation in inhibin B which is released by an increased number of arrested ovarian follicles.
  - - - Presentation: Serum PRL > 25 ng/ml (N < 20 ng/ml) -> decreased kisspeptin -> Inhibition of pulsatile GnRH -> lowers serum FSH, LH, and estradiol levels. Inadequate E2 from endometrial proliferation -> amenorrhea. SEE PAGE 740 DIAGRAM. There is sufficient enough E2 to maintain TS-4 breasts. ,marginal E2 for milk production. Only 20-30% have galactorrhea. Inadequate E2 for normal bone density -> premature osteoporosis.
      - Causes: Pituitary stalk compression (craniopharyngioma, meningioma, or a nonfunctioning pituitary macro adenoma). Medications (phenothiazines, cimetidine, metoclopramide). Primary hypothyroidism -> increased prolactin secretion (due to increased TRH release from decreased TH).
    - - Mediators: Intense exercise -> increased opioids (B-endorphins) -> decreased pulsatile GnRH. Stress -> increased CRH -> increased cortisol -> decreased pulsatile GnRH. Anorexia nervosa, buimia -> decreased insulin and leptin -> decreased pulsatile GnRH when combined with increased NPY. SEE PAGE 738-740.
      - Mild GnRH reduction vs Severe GnRH reduction: Mild- chronic anovulation due to low LH. Severe- chronic amenorrhea due to low FSH.
      - Treatment: Control diet, exercise and stress. Combined OCPs to prevent osteoporosis. Pulsatile GnRH or clomiphene to induce fertility.
      - Serum E2 level is 25-30 pg/ml (N>50). Adequate to maintain breast tissue and prevent hot flashes. Inadequate to maintain bone density (-> early onset osteoporosis).