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Menopause

Berek & Novak's Gynecology — Chapter 18 (Shifren & Schiff)

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Definition & Epidemiology

• Menopause = permanent cessation of menstruation due to ovarian failure
• Average age: 52 years (range 40–58)
• Age at menopause is genetically determined and unaffected by age at menarche or use of oral contraceptives
• Women in the developed world spend >30 years (>1/3 of their life) beyond menopause
• Premature menopause = before age 40 (also called premature ovarian insufficiency)

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Health Concerns After Menopause

1. Vasomotor Symptoms (VMS)

• Affect up to 75% of perimenopausal women
• Most last 1–2 years, but may persist ≥10 years
• Hot flashes are the primary reason women seek menopausal care

• Central event (likely hypothalamic) → ↑ core body temperature → peripheral vasodilation + sweating
• Triggered by noradrenergic, serotonergic, and/or dopaminergic activation
• KNDy neurons (kisspeptin, neurokinin B, dynorphin) play a key role — peripheral NKB infusion induces a typical hot flash; blocking NKB reduces them
• VMS are due to estrogen withdrawal, not simply estrogen deficiency
  • Example: Turner syndrome patients (high FSH, low estrogen) have no hot flashes until estrogen is given and then withdrawn

Hormone therapy is the most effective treatment for VMS.

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2. Genitourinary Syndrome of Menopause (GSM)

• Affects at least 60% (some reports ≥50%) of menopausal women
• Encompasses anatomic changes + symptoms affecting labia, vagina, urethra, and bladder due to estrogen deficiency
• Symptoms: genital dryness, irritation, burning; dysuria, urgency, recurrent UTIs; dyspareunia
• Unlike VMS, GSM worsens with time in the absence of treatment

• First-line non-hormonal: Vaginal lubricants (water/silicone/oil-based) + vaginal moisturizers 2–3×/week
• Pelvic PT and vaginal dilators for severe dyspareunia
• Topical estrogen (preferred if no VMS): Low-dose vaginal estradiol cream, tablet (10 µg or 4 µg), or ring (7.5 µg/day)
  • Minimal systemic absorption; safe; no concurrent progestin needed
  • No increased endometrial, breast cancer, or CVD risk confirmed in WHI observational data (n > 45,000)
• Vaginal DHEA (0.5% daily, prasterone) — approved for moderate-to-severe dyspareunia; serum hormone levels remain in postmenopausal range
• Ospemifene (60 mg/day oral SERM) — approved for moderate-to-severe dyspareunia from VVA; improves sexual function, confirmed endometrial safety

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3. Sexual Dysfunction

• Sexual concerns are common after menopause; etiology is multifactorial
• Effective treatment options exist

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4. Osteoporosis

• Risk increases markedly at menopause
• Pharmacologic treatment indicated for: T-score < –2.5; prior hip/vertebral fracture; low BMD at high fracture risk (by FRAX tool)

Combined calcium + vitamin D with even very low-dose ET (CE 0.3 mg/day or transdermal E2 0.014 mg/day) produces significant BMD gains vs. placebo.

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5. Cardiovascular Disease

• Important health concern for menopausal women
• Timing hypothesis: Early HT initiation (closer to menopause, when less atherosclerosis is present) yields more favorable CV risk-benefit profile
• ELITE trial: HT initiated within 6 years of menopause → slower CIMT progression; no effect if started >10 years after menopause
• Lifestyle interventions + management of hyperlipidemia, hypertension, and diabetes are essential

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6. Breast Cancer

• Most common cancer in women; #2 cause of cancer death
• Lifetime risk: 12%
• Risk factors: age, family history, early menarche, late menopause, genetic mutations (BRCA), prior epithelial atypia
• EPT (estrogen + progestin): WHI showed increased breast cancer risk
• ET alone: WHI showed reduced risk during poststopping phase
• Screening: mammography starting at age 40 (no later than 50); every 1–2 years; continue at least to age 75

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7. Dementia / Cognitive Decline

• Highly prevalent in older women
• Depression can cause pseudodementia (characterized by reported, not hidden, memory loss)
• Risk reduction should be optimized; role of HT in dementia prevention remains uncertain

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Hormone Therapy (HT)

Regimens

• Women without a uterus: Estrogen alone (ET)
• Women with a uterus: Combined estrogen + progestin (EPT) — unopposed estrogen → endometrial hyperplasia and cancer
  • Sequential: Estrogen daily + progestin 12–14 days/month → predictable bleeding
  • Continuous-combined: Daily estrogen + lower-dose progestin → amenorrhea in most by 1 year

Routes

• Oral: Standard; first-pass hepatic effect → ↑ sex hormone-binding globulin (SHBG), ↑ triglycerides, ↑ clotting factors
• Transdermal (patch, gel, spray, intravaginal ring): Avoids first-pass effect; no change in SHBG → free testosterone preserved (benefit for libido); no increased VTE risk in observational studies; lower gallbladder disease risk

Bioidentical Hormones

• Refer to hormones structurally identical to ovarian hormones (estradiol, progesterone)
• FDA-approved oral and transdermal estradiol + oral micronized progesterone available
• Custom-compounded "bioidentical" preparations: potentially significant risk with no known added benefit — should be avoided; FDA-approved formulations preferred

Contraindications to HT

WHI Findings (Key Summary)

• Overall absolute risk of adverse events was considerably lower in women aged 50–59 than older women
• Both EPT and ET associated with: ↓ VMS, ↓ diabetes, ↓ hip fractures; ↑ VTE, ↑ gallbladder disease, ↑ stroke
• EPT → ↑ breast cancer risk; ET → ↓ breast cancer risk (poststopping phase)
• Neither EPT nor ET was associated with increased all-cause, cancer, or CV mortality at 18 years of follow-up
• WHI used only oral CE + MPA — results may not apply to transdermal estradiol or other progestins

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Menopausal Mood and Mental Health

• Menopause may have mood effects in some women — partly secondary to sleep disruption from hot flashes
• SSRIs may both treat depression and ameliorate hot flashes
• Patients with prior PMS or postpartum depression are at higher risk for perimenopausal depression
• All menopausal women with depression should be assessed for psychosocial precipitants and domestic abuse

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Source: Berek & Novak's Gynecology (Berek & Novak's Gynecology, Chapter 18), Jan L. Shifren & Isaac Schiff

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CHAPTER 10 — Family Planning & Contraceptives

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Key Points

1. Most common US contraceptive methods: sterilization > oral contraceptives (OCs) > condoms
2. Latex condoms reduce risk of STDs and cervical cancer
3. IUDs are as effective as tubal sterilization with no increased long-term pelvic infection risk
4. Combination OC/patch/vaginal ring increase risk of venous thrombosis and thromboembolism
5. Low-dose estrogen–progestin OCs do not increase heart attack risk in nonsmokers <35 years with no vascular risk factors
6. OCs do not substantially increase breast cancer risk; benefits outweigh risks for most women
7. Progestin-only injectables/implants achieve very low pregnancy rates without estrogen-associated VTE risk
8. Hormonal contraceptives reduce risk of endometrial and ovarian cancer

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Contraceptive Efficacy (Table 14-1 — % Unintended Pregnancy in Year 1)

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A. Non-Hormonal Methods

1. Coitus Interruptus

• Withdrawal of penis before ejaculation
• 4/100 women (perfect use) to 22/100 (typical use) per year
• No cost; immediately available

2. Breastfeeding (Lactational Amenorrhea)

• Suckling → ↑ prolactin → ↓ GnRH → ↓ LH → inhibits follicular maturation
• Effective only if: fully breastfeeding, amenorrheic, infant <6 months
• Feeding intervals must not exceed 4 hours (day) or 6 hours (night)
• 6-month pregnancy rate: 0.45–2.45%

3. Fertility Awareness Methods

• Calendar, standard days, two-day, ovulation/symptothermal methods
• Typical use: 24%; TwoDay method perfect use: 5%

4. Condoms

• Male latex condom: 18% typical / 2% perfect use
• Only method providing dual protection against STDs and pregnancy

5. Vaginal Spermicides

• N-9 (nonoxynol-9) is toxic to sperm and to lactobacilli
• Regular use → ↑ vaginal E. coli colonization → ↑ E. coli bacteriuria risk

6. Vaginal Barriers

• Circular latex dome; requires practitioner fitting (sizes 65, 70, 75 fit most women)
• Must be used with spermicide; left in place ≥6 hours after intercourse
• Caya (FDA 2014): single-size silicone diaphragm; no fitting required; used with spermicide
• Complications: ↑ bladder infection risk; do not dust with talc (ovarian cancer risk)

• More effective in nulliparous than parous women

• Contains N-9; worn up to 24 hours

7. Intrauterine Contraception (IUDs)

• Copper T380A (ParaGard): lasts ≥10 years; most effective non-hormonal method; also used for emergency contraception up to 5 days after unprotected sex
• LNG-IUS (Mirena, Kyleena, Liletta, Skyla): releases levonorgestrel; reduces menstrual bleeding; ≥3–8 years depending on device
• No increased long-term pelvic infection risk

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B. Hormonal Contraception

Mechanism

• ALL hormonal contraceptives are progestin-dominant — progestin does the real contraceptive work:
  • Suppresses ovulation
  • Thickens cervical mucus
• Estrogen component: improves cycle control; adds to ovarian suppression

Progestins

• Synthetic progesterone analogues
• Differ in affinity for estrogen, androgen, and progesterone receptors
• Androgenic progestins (norethindrone, levonorgestrel) → adverse lipid effects
• Less androgenic (desogestrel, norgestimate, drospirenone) → better lipid profile

Combination Oral Contraceptives (OCs)

• Monophasic (same dose daily) or multiphasic (varying doses)
• Packaged as 21/7 or 24/4 (preferred — 4-day placebo interval → better ovarian suppression)
• Extended-cycle (active pills for 3 months): fewer headache/dysmenorrhea episodes
• Continuous-cycle (365 days): amenorrhea; preferred for endometriosis/chronic pelvic pain

Non-Contraceptive Benefits of OCs

• ↓ Dysmenorrhea, menorrhagia, iron deficiency anemia
• ↓ Ovarian cysts
• ↓ Endometrial and ovarian cancer risk (significant)
• ↓ PMS/PMDD symptoms
• Improvement of acne (especially with drospirenone-containing OCs)

Cardiovascular Risks

Other OC Effects

• Blood pressure: Low-dose pills minimal effect; surveillance advised
• Lipids: Estrogen ↑ HDL, ↓ LDL; androgenic progestins antagonize this
• Glucose: Older high-dose progestins → insulin antagonism; low-dose modern OCs minimal effect
• Return of fertility: May delay ovulation a few months; >6 months amenorrhea → evaluate for prolactinoma
• Teratogenicity: No increased risk of malformations

Drug Interactions With OCs

• Reduce OC efficacy (↑ CYP450 enzymes): Rifampin, phenytoin, phenobarbital, carbamazepine, oxcarbazepine, St. John's Wort, griseofulvin
• No effect: Valproic acid, lamotrigine, gabapentin, levetiracetam
• OCs affect other drugs: ↑ Half-life of diazepam, alprazolam; ↑ theophylline/caffeine levels; ↑ cyclosporine levels

Other Hormonal Methods

Emergency Contraception

• Levonorgestrel 1.5 mg (Plan B): most effective within 72 hours; up to 120 hours
• Ulipristal acetate 30 mg (ella): selective progesterone receptor modulator; effective up to 120 hours; possibly more effective than LNG in obese women
• Copper IUD: most effective EC; works up to 5 days after unprotected sex

Long-Acting Reversible Contraceptives (LARCs)

• "Forgettable" methods: typical-use pregnancy rate <1%
• Include: etonogestrel implant, LNG-IUS, copper IUD
• Recommended as first-line for adolescents (endorsed by ACOG)

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C. Sterilization

• Failure rate: 0.5% (10-year cumulative ~1.85%)
• Methods: bipolar coagulation, rings, clips, salpingectomy (now recommended for ↓ ovarian cancer risk)
• Can be performed postpartum, postabortion, or interval

• Failure rate 0.15% typical / 0.10% perfect
• Simpler, safer, and cheaper than female sterilization
• Requires confirmation of azoospermia (~20 ejaculations post-procedure)

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CHAPTER 29 — Puberty

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Key Points

1. Normal pubertal development occurs in predictable, orderly sequence over a definite time frame
2. Earliest pubertal changes on average at age 10; normal range is wide
3. Delayed puberty is often constitutional but underlying pathology must be investigated
4. Asynchronous puberty (breasts without pubic/axillary hair) = usually androgen insensitivity syndrome
5. Most common cause of precocious puberty = constitutional (idiopathic)
6. Most common cause of heterosexual development at expected puberty age = PCOS

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Normal Pubertal Development

• Resetting of the classic negative gonadal steroid feedback loop
• Altered circadian and ultradian gonadotropin rhythms
• Acquisition of a positive estrogen feedback loop → midcycle LH surge → ovulation

1. Accelerated growth (first detectable sign)
2. Breast budding (thelarche) — usually first recognized sign
3. Pubic hair appearance
4. Peak growth velocity
5. Menarche (average age ~12.5 years)

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Tanner Stages

Breast Development

Pubic Hair Development

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Mechanisms Underlying Puberty

1. CNS inhibition of puberty → lifts at appropriate time
2. GnRH pulse generator (medial basal hypothalamus) is reactivated → ↑ GnRH pulse amplitude and frequency → ↑ gonadotropins → ↑ gonadal steroids
3. Two-stage HPG axis development:
   • Early puberty: ↓ sensitivity to negative feedback from low circulating sex steroids
   • Late puberty: maturation of positive estrogen feedback → midcycle LH surge
4. Gatekeepers: Kisspeptin and neurokinin B
5. Metabolic modifiers: Leptin and nesfatin-1 can alter gatekeeper activity

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Aberrations of Pubertal Development (Table 8-1)

Classification

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Delayed or Interrupted Puberty

• Chronic diseases: celiac disease, Crohn's, sickle cell anemia, cystic fibrosis
• Hypergonadotropic hypogonadism (FSH >30 mIU/mL): Turner syndrome, pure gonadal dysgenesis (46,XX or 46,XY), early gonadal failure
• Hypogonadotropic hypogonadism (LH + FSH <10 mIU/mL): Hypothalamic/pituitary causes, Kallmann syndrome
• Anatomic: imperforate hymen, transverse vaginal septum, Müllerian agenesis (MRKH syndrome)

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Asynchronous Puberty — Androgen Insensitivity Syndrome (AIS)

• Breast development (usually only to Tanner 3) without significant pubic/axillary hair
• 46,XY karyotype; bilateral testes; female external genitalia; blind-ending vagina; no Müllerian derivatives (uterus absent)
• AMH made by Sertoli cells → Müllerian regression normal
• 50% develop inguinal hernias → karyotype any girl with inguinal hernia
• Risk of germ cell malignancy: 2% → gonadectomy after pubertal feminization (usually after age 25)
• Diagnosis: ↑ testosterone (male levels), ↑ LH, normal FSH + 46,XY karyotype

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Precocious Puberty

• Gonadotropin-dependent (Central/True): GnRH prematurely activates HPG axis
• Gonadotropin-independent (Peripheral/Pseudopuberty): Peripheral sex steroid secretion

1. Constitutional (idiopathic) — most common
2. Hypothalamic neoplasms (especially hamartomas)
3. Congenital malformations
4. Infiltrative processes (Langerhans cell histiocytosis)
5. Post-irradiation, trauma, or infection

1. Autonomous gonadal hypersecretion (cysts, McCune–Albright syndrome)
2. Congenital adrenal hyperplasia (21-hydroxylase, 11β-hydroxylase, 3β-HSD deficiency)
3. Iatrogenic estrogen/androgen exposure
4. Hypothyroidism (primary)
5. Gonadotropin-secreting neoplasms (HCG-secreting: pinealomas, choriocarcinoma, teratomas, hepatoblastomas)
6. Gonadal neoplasms (granulosa-theca cell tumors, Sertoli-Leydig cell tumors)
7. Adrenal neoplasms (adenomas, carcinomas)

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Premature Thelarche

• Uni/bilateral breast enlargement without other signs of maturation
• Usually by age 2; rarely after age 4
• Mechanism: ↑ breast sensitivity to low estrogen OR follicular cysts
• Benign and self-limited → reassurance + follow-up only
• Uterine volume measurement may distinguish from true precocious puberty

Premature Adrenarche (Pubarche)

• Pubic hair before age 8 without breast development
• ↑ Risk of PCOS, hyperinsulinemia, acanthosis nigricans, dyslipidemia in adolescence
• May be first sign of insulin resistance

Isolated Premature Menarche

• Vaginal bleeding age 1–9 without other puberty signs
• Differential: foreign body, trauma, abuse, infection, neoplasm (rhabdomyosarcoma), McCune–Albright, hypothyroidism
• Usually followed by normal puberty and fertility

Heterosexual Puberty

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Premenstrual Symptoms (PMS / PMDD)

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Key Concepts

• No specific serum hormone level directly causes PMS/PMDD — a subgroup of women are vulnerable to hormonal changes, not absolute levels
• Correlation exists between the degree of hormonal change (pre/postpartum) and incidence of mood disorders
• Women vulnerable to hormonal changes may experience: PMS, postpartum depression, perimenopausal depression, OC-associated mood changes

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PMS vs. PMDD

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DSM-5 Criteria for PMDD (F32.81)

• ≥5 symptoms in the majority of menstrual cycles, occurring most of the time during the premenstrual week
• Symptoms improve within a few days of menses onset and are minimal/absent in the postmenstrual week

• Marked affective lability
• Marked irritability/anger/interpersonal conflict
• Marked depressed mood/hopelessness/self-deprecating thoughts
• Marked anxiety/tension

• Decreased interest in usual activities
• Difficulty concentrating
• Lethargy
• Marked appetite change
• Hypersomnia or insomnia
• Feeling overwhelmed or out of control
• Physical symptoms (bloating, breast tenderness)

• Symptoms markedly interfere with work, family, or academic life
• Not an exacerbation of another disorder
• Must be corroborated by ≥2 months of prospective daily ratings
• Screen for domestic abuse and psychosocial factors

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Treatment

Non-Pharmacologic (PMS)

• Calcium 1,200–1,600 mg/day (divided doses): well-supported; reduces luteal phase symptoms
• Vitamin B6 ≤100 mg/day: modest evidence; reasonable to support; peripheral neuropathy at ≥200 mg/day
• Magnesium 200–400 mg/day ± vitamin B6 50 mg: some evidence; counteracts calcium's constipating effect; caution in renal insufficiency
• Omega-3 fatty acids (EPA+DHA, 3 g/day): anti-inflammatory; may help mood/depression component; anticoagulant effect
• Chaste Tree (Vitex agnus-castus): historically used for menstrual disorders; some positive RCT data
• Lifestyle: eliminate caffeine, smoking cessation, regular exercise, regular meals (complex carbohydrates), adequate sleep, stress reduction (meditation, yoga)
• No treatment for PMS has been validated by rigorous empirical studies (including St. John's Wort — contradictory evidence)

Pharmacologic (PMDD) — Table 23-2

Note: SSRIs can be given continuously or only during the luteal phase (2 weeks before menses). Luteal-phase dosing is effective and reduces side effects. Hormonal interventions (OCs, GnRH agonists): must carefully monitor as hormones can either improve or exacerbate mood symptoms in vulnerable women.

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*Source: Berek & Novak's Gynecology, Chapters 14 (Family Planning), 8 (Puberty), 23 (Psychiatric Aspects of Reproductive Health)*Your credits are exhausted. Your daily credits reset tomorrow, or you can purchase a top-up for more.