INFLUENCE OF GONADAL HORMONES ON THE FEMALE REPRODUCTIVE CYCLE FROM BIRTH TO OLD AGE

General Overview

• Primary gonadal hormones (estrogens, progestogens) maintain and nourish the reproductive tract and have widespread effects (skin, hair, skeleton, vascular, electrolytes, mood).
• Ovarian secretions (chiefly estrogens) are crucial at every life phase: infancy, childhood, puberty, adult reproductive years, and senescence.

INFANCY

Newborn Estrogen Effects

• High maternal estrogen crosses placenta → noticeable effects in the female neonate:
  • Breast enlargement (“witch’s milk” sometimes exuded).
  • External genitalia appear somewhat developed.
  • Endometrium stimulated to proliferate.
  • Vaginal epithelium: Stratified, cornified cells (estrogenic).
• Regression After Birth:
  • Within ~1 week, these signs recede (low estrogen levels).
  • Newborn ovaries: small, containing only primordial follicles; cannot produce significant estrogens.

CHILDHOOD (Postnatal Recess to Pre-Puberty)

1. Ovarian Changes
   • Gradual increase in interstitial tissue (fibrous stroma) as many follicles undergo atresia.
   • No functional follicular development capable of significant estrogen output.
2. Vaginal Cytology
   • Shows predominantly basal/parabasal cells with bacteria/debris.
   • No estrogen-induced cornification.
3. Breasts
   • Remain infantile (no glandular development).

PUBERTY (Sexual Maturation)

1. Early Pubertal Changes
   • Uterus: First to respond to estrogens (endometrial proliferation with straight tubular glands).
   • Vagina: Thickens, becomes stratified; cornified cells in smears.
   • Ovarian Follicles: Progress beyond minimal layers → multiple granulosa layers, theca interna forming.
   • Breasts: Areola pigmentation; conical protuberance (thelarche).
   • Body Contours: Fat deposition (shoulders, hips, buttocks).
   • Hair: Adult pubic/axillary patterns begin.
2. Gonadotropin-Ovarian Interplay
   • Pituitary FSH and LH must cycle appropriately with ovarian estrogen/progesterone to establish ovulatory cycles.
   • Adolescence and menopause can feature irregular, often anovulatory cycles.
3. Menstrual Cycle Onset
   • Occurs with rhythmic ovulatory cycles after some months/years of initial irregularities.

ADULT REPRODUCTIVE YEARS

Mature Menstrual Cycle (28-day typical example)

1. Menstrual Phase (days ~1–4)
   • Upper two-thirds of endometrium sloughed in 48–72 hrs.
   • Endometrial surface rapidly repaired under rising estrogen from developing follicles.
   • Vaginal smear: minimal estrogen effect.
2. Follicular (Proliferative) Phase (days ~5–13)
   • Ovarian follicles develop under FSH → produce estrogen.
   • Endometrium thickens, glands elongate.
   • Vaginal epithelium: progressively cornified cells.
   • One follicle typically achieves dominance by ~day 12.
3. Ovulation (day ~14)
   • LH surge triggers ovulation of mature follicle.
   • Rapid formation of corpus luteum → secretes progesterone (+some estrogen).
4. Luteal (Secretory) Phase (days ~15–26)
   • Endometrial glands: sawtooth secretory changes under progesterone.
   • Vaginal smear: decreased superficial estrogenic cells, more folded intermediate cells (progesterone effect).
   • If no fertilization, corpus luteum regresses ~day 26 → drop in progesterone/estrogen.
5. Premenstrual (days ~26–28)
   • Rapid hormone withdrawal → endometrium ischemic, breaks → menstruation day 28.

Additional Changes

• Breasts: Fully mature, with duct extension (estrogen) + alveoli (progesterone).
• Premenstrual Edema: Estrogen and progesterone can cause generalized fluid retention, recognized as bloating/weight gain.

Pregnancy

1. Conception & Early Placental Hormones
   • Chorionic gonadotropin (hCG) from implanted embryo maintains corpus luteum → continued estrogen/progesterone production for first ~3 months.
   • Placenta takes over steroidogenesis after ~12 weeks.
2. High, Increasing Estrogen & Progesterone → no new ovulation (FSH/LH suppressed).
3. Breasts: Duct/alveolar proliferation (with pituitary prolactin); no full lactation until postpartum.
4. Vaginal Cytology: High progesterone → “navicular cells” in smears.
5. Puerperium: Post-delivery, large estrogen/progesterone withdrawal.
   • Prolactin + suckling reflex → lactation onset.
   • Ovarian cycles suppressed in lactation (varies from months to >1 year).

MENOPAUSE AND SENESCENCE

1. Menopause:
   • Average ~51.4 years.
   • Ovaries lose functional follicles → low estrogen → high FSH (lack of negative feedback).
   • Physical changes: atrophy of breasts, uterus, vagina; bone loss; skin thinning; vasomotor symptoms.
2. Premature Ovarian Failure:
   • Primary hypogonadism <40 years.
   • Similar changes to menopause.
3. Senile Changes
   • Childhood and old age are relatively “quiet” gonadal phases.
   • Without sufficient estrogen, many tissues revert to atrophic states (bone loss, dryness).

FUNCTIONAL AND PATHOLOGIC CAUSES OF UTERINE BLEEDING

Normal Menstrual Bleeding

1. Definition
   • The uterus is unique in undergoing cyclical necrosis and desquamation with bleeding as a healthy process.
   • Menstruation: Regular shedding of the superficial endometrium in response to rhythmic ovarian steroid (estrogen, progesterone) production.
2. Characteristics
   • Typically 2–7 days duration, <80 mL total blood loss.
   • Regular cycles: Evidence of a well-ordered hormonal interplay (pituitary-ovarian-endometrial axis).

ABNORMAL UTERINE BLEEDING (Menorrhagia, Metrorrhagia)

Terminology

• Menorrhagia: Heavy or prolonged menstrual flow.
• Metrorrhagia: Bleeding at irregular intervals (spotting/bleeding between normal flows).

General Pathophysiologic Concepts

1. Withdrawal Bleeding
   • Normal cycle: At end of luteal phase, corpus luteum regresses → drop in estrogen/progesterone → endometrial shedding.
2. Anovulatory Cycles
   • Persistent estrogen production without ovulation → endometrium proliferates excessively.
   • Eventually, random estrogen dips or “breakthrough bleeding” occur, leading to unpredictable flow.
   • Common in adolescence, perimenopause, polycystic ovary syndrome (PCOS), weight loss, strenuous exercise, thyroid dysfunction, advanced liver/renal disease.
3. Disordered Endometrial Responses
   • Mixed proliferative + secretory patterns (e.g., abnormal luteal phases).
   • Prolonged unopposed estrogen → endometrial hyperplasia; sporadic estrogen reduction triggers bleeding.

SPECIFIC CAUSES OF UTERINE BLEEDING

1. Non-Uterine Genital Tract Causes

• Ovaries, Fallopian Tubes:
  • Ovarian cysts/tumors secreting hormones → abnormal bleeding.
• Cervix, Vagina, Vulva, Urethra, Bladder, Bowel:
  • Cervical polyps, cervical cancer (often postcoital spotting, not heavy).
  • Traumas or fistulas from adjacent structures.

2. Local Uterine Pathologies

• Polyps: Endometrial or cervical polyps.
• Leiomyomas (Fibroids): Benign uterine smooth muscle tumors causing heavy/prolonged bleeding.
• Adenomyosis: Endometrial tissue within the uterine muscle, leading to menorrhagia/dysmenorrhea.
• Uterine Scar Defects: e.g., hysterotomy scar.
• Malignancies:
  • Endometrial adenocarcinoma, uterine sarcoma, cervical cancer.
  • Metastatic disease to endometrium.
• Uterine AVM (Arteriovenous Malformation): Rare cause of profuse bleeding.
• Endometritis / PID: Infectious/inflammatory conditions.

3. Pregnancy-Related

• Placenta Previa, Abruptio Placentae (premature separation), Spontaneous/Induced Abortions.
• Ectopic Gestation: Implantation outside uterine cavity can present with bleeding.
• Gestational Trophoblastic Disease: e.g., hydatidiform mole, choriocarcinoma.

4. Systemic Conditions

• Bleeding Diatheses: e.g., von Willebrand disease, factor deficiencies, platelet function disorders.
• Coagulopathy: e.g., advanced liver disease, or use of anticoagulants.
• Acute Leukemia: Thrombocytopenia → abnormal uterine bleeding.
• Endocrine Disorders: Hypothyroidism, hyperthyroidism, hyperprolactinemia, Cushing syndrome can cause menstrual irregularities.
• Chronic Illness: e.g., advanced renal disease associated with anovulation.

KEY PHYSIOLOGIC PATHWAY

1. Normal Cycle
   • Follicular Phase: Rising estrogen → endometrial proliferation.
   • Ovulation (LH surge) ~ day 14 (in a 28-day cycle).
   • Luteal Phase: Corpus luteum secretes progesterone (and some estrogen) → secretory changes in endometrium.
   • No Pregnancy: Hormones ↓ → endometrial ischemia → shedding (menstruation).
2. Pathologic Bleeding arises from:
   • Hormonal Imbalance (e.g., anovulation, unopposed estrogen, suboptimal progesterone).
   • Uterine Structural Lesions (polyps, fibroids, adenomyosis).
   • Malignant/Pre-malignant changes (endometrial hyperplasia, carcinoma).
   • Pregnancy-Related or Systemic issues (bleeding disorders, endocrine pathology).