Reproductive Pathophysiology: Common Disorders

what happens to estrogen, inhibins, LH, and FSH during menopause

decrease

what estrogen can still be produced after menopause

estrone produced in adipose tissue

signs and symptoms of menopause

• vasomotor changes

• hot flashes

• sweating

• irritability/sleep problems

• atrophy of estrogen-dependent tissue (vaginal dryness)

Treatment options for menopause

• HRT → only for vasomotor symptoms or dryness at the lowest possible dose for shortest period of time

• estrogen and progesterone → better option

LH hypothesis for PCOS

high levels of LH in presence of normal-low levels of FSH and estradiol; LH stimulates thecal cells to synthesize androgen androstenedione

• increase LH and androgens = disrupt follicle growth and production of estrogen

• no estrogen → no LH surge → no ovulation

insulin hypothesis for PCOS

increase insulin secretion = decrease sex hormone binding globulin (SHBG) and increase 5-alpha reductase activity (testosterone →DHT)

• increase levels of free androgens = androgenic effect

ovarian hypothesis for PCOS

dysregulation of sex steroid synthesis in thecal cells

• FSH in granulosa cells can become less sensitive to LH and doesn’t produce enough estrogens

signs and symptoms of PCOS

• anovulation or oligo-ovulation

• increased plasma levels of plasma androgens (hirsutism/acne)

• appearance of polycystic ovaries

treatment options for PCOS

• contraceptives with estrogen and progesterone

• androgen receptor antagonists (helps treat hirsutism)

pathophysiology of endometriosis

proliferation of endometriotic tissue outside the uterus; express more estrogen receptors and down regulation of progesterone

how does endometriosis occur

retrograde menstruation → reflux of menstrual debris containing endometrial cells thru fallopian tubes into peritoneal cavity (these cells survive and proliferate)

coelomic metaplasia

peritoneal mesothelial cells transforms into glandular endometrium; promoted by hormonal and immunological factors

lymphatic/vascular dissemination

transport of cells via lymphatic and blood vessels

signs and symptoms of endometriosis

• heterogenous and non-specific

• dysmenhorrhea (pain during menstruation)

• chronic pelvic pain and/or back pain

• infertility

treatment options for endometriosis

first line = estrogen and progesterone + NSAIDs (inflammation)

progesterone alone = stops periods and growth of endometrial implants

• severe = GnRH agonists / antagonists with low-dose estrogen

• alternative = aromatase inhibitors

pathophysiology of uterine fibroids

• progesterone receptors are up regulated in tumors and aromatase = up regulated

• dysregulation of fibrotic growth factors

• abnormalities of ECM

• gonadal steroids promotes the growth of uterine tissue

signs and symptoms of uterine fibroids

• heavy menstrual bleeding

• pelvic pressure/pain

• frequent urination/ difficulty emptying bladder

• constipation

• low back pain

• painful intercourse

treatment options for uterine fibroids

• combined oral contraceptives

• IUD progestin

• GnRH agonists

• Selective Progesterone Receptor Modulators (SPRMs) → Europe

surgical procedures for uterine fibroids

• myomectomy

• hysterectomy

• uterine artery embolization

• Magnetic Resonance-guided Focused Ultrasound Surgery (MRgFUS)

70% of breast cancers fall under what category

positive for estrogen receptor (ER) and depend on ER signaling

MOA of SERMS for treating breast cancer

act as agonist/antagonist depending on tissue

i.e. tamoxifen = antagonist in breast tissue; agonist in endometrial tissue (risk) and partial agonist in bone (risk for osteoporosis)

MOA of aromatase inhibitors for treating breast cancer

prevents conversion of androgen → estrogen with aromatase enzyme

MOA of SERD for treating breast cancer

selective estrogen receptor degrader; binds to the receptor and induces degradation of the receptor (less signaling over time)

• increased risk for endometrial cancer

• increased risk for thromboembolic events

• increased incidence of cataracts

causative factor for BPH

altered levels and balance of androgens, estrogens, and gonadotropins

proliferative factor for BPH

androgens

what other changes occur in BPH

• autocrine and paracrine factors

• insulin-like GF

• epidermal GF

• FGF

• TGF-beta

• systemic and localized inflammation

signs and symptoms of BPH

• frequent urination

• urinary urgency

• nocturia

• straining to urinate

• weak stream

• incomplete emptying of bladder

treatment options for BPH

• lifestyle changes = first line

• limit fluid intake before bed and travel

• limit intake of caffeine and alcohol (diuretics)

• increase activity and wt control

pharmacologic treatment options for BPH

• 5-alpha reductase inhibitors → decrease DHT production and decrease size of prostate

• alpha 1 antagonist or beta-1 agonist → relax smooth muscle