25.1 Reproductive Endocrinology & Menstrual Disorders: The Menstrual Cycle, Puberty, Abnormal Uterine Bleeding (PALM-COEIN), Amenorrhea, PCOS, Hyperprolactinemia, Dysmenorrhea, Infertility, Menopause, HRT and Osteoporosis

Why this area matters

TOS area Q asks you to:

• explain the actions of female hormones, the onset of puberty and the menstrual cycle, secondary sex characteristics and breast development;
• recognize amenorrhea and infertility;
• diagnose disorders of later life such as osteoporosis;
• plan treatment, including hormone therapy and bisphosphonates, with their side effects.

TOS area S covers menstrual disorders:

• amenorrhea;
• abnormal uterine bleeding, endometrial polyps and endometrial hyperplasia;
• bleeding from an immature hypothalamic-pituitary-ovarian (HPO) axis;
• drug-induced bleeding;
• blood dyscrasias.

Menstrual complaints are among the most common gynecologic consultations, and infertility affects a substantial minority of Filipino couples.

Menstrual Cycle Physiology

The normal menstrual cycle has an average duration of 28 days (normal range 21 to 35 days) and reflects coordinated neuroendocrine feedback between the hypothalamus, anterior pituitary gland, and ovaries (the HPO axis).

Ovarian and Endometrial Cycles

1. The Follicular (Proliferative) Phase:
   • Days 1 to 14: Pulsatile gonadotropin-releasing hormone (GnRH) from the arcuate nucleus of the hypothalamus stimulates anterior pituitary secretion of Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH).
   • FSH recruits a cohort of antral follicles. Under FSH stimulation, granulosa cells express aromatase, converting theca-cell-derived androgens into Estradiol ($E_2$).
   • The follicle with the highest aromatase activity and FSH receptor density becomes the dominant follicle (Graafian follicle). Rising estradiol induces the proliferative phase of the endometrium, promoting glandular mitosis and elongation of spiral arteries.
   • The LH Surge: As circulating estradiol levels exceed 200 pg/mL for at least 48 hours, feedback on the pituitary switches from negative to positive feedback. This triggers a massive mid-cycle LH surge. The LH surge induces resumption and completion of meiosis I (arrested in prophase I since fetal life) with extrusion of the first polar body; the oocyte then arrests in metaphase II until fertilization. Ovulation occurs 24 to 36 hours after the onset of the LH surge (or 10 to 12 hours after its peak).
2. The Luteal (Secretory) Phase:
   • Days 14 to 28: The ruptured Graafian follicle transforms into the Corpus Luteum, which produces copious Progesterone and moderate estradiol.
   • Progesterone converts the proliferative endometrium into the secretory endometrium, characterized by tortuous glycogen-rich glands and stromal decidualization, preparing for blastocyst implantation.
   • The luteal phase is relatively constant at about 14 days, so variation in cycle length comes mainly from the follicular phase. In the absence of human chorionic gonadotropin (hCG) from an implanting blastocyst, the corpus luteum undergoes luteolysis, degenerating into the fibrous corpus albicans.
   • Menstruation: Abrupt withdrawal of progesterone and estradiol triggers intense vasospasm of the endometrial spiral arterioles, causing ischemic necrosis, lysosomal enzyme release, and shedding of the functional layer of the endometrium (stratum functionale).

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Abnormal Uterine Bleeding (AUB) — The FIGO PALM-COEIN Classification

Abnormal Uterine Bleeding in non-gestational reproductive-aged women is categorized by the International Federation of Gynecology and Obstetrics (FIGO) into structural and non-structural etiologies:

PALM: Structural Etiologies (Identified via Imaging or Histopathology)

• P - Polyp (AUB-P): Benign endometrial or endocervical overgrowths of stroma and blood vessels. Diagnosed via saline infusion sonohysterography (SIS) or hysteroscopy; treated with hysteroscopic polypectomy.
• A - Adenomyosis (AUB-A): Ectopic presence of endometrial glands and stroma within the myometrium, accompanied by reactive smooth muscle hypertrophy. Classically presents in multiparous women in their 40s with heavy menstrual bleeding and severe secondary dysmenorrhea. Pelvic exam reveals a globular, symmetrically enlarged, soft, boggy, and tender uterus.
• L - Leiomyoma (AUB-L / Uterine Fibroids): Benign monoclonal smooth muscle neoplasms. Subclassified by location: submucosal (most strongly linked to heavy bleeding and recurrent pregnancy loss), intramural (most common overall), and subserosal (often asymptomatic or causing urinary/rectal bulk symptoms).
• M - Malignancy & Hyperplasia (AUB-M): Endometrial atypical hyperplasia / endometrial intraepithelial neoplasia (EIN) and endometrial carcinoma. Postmenopausal bleeding is the cardinal symptom.

COEIN: Non-Structural Etiologies (Systemic or Functional)

• C - Coagulopathy (AUB-C): Systemic disorders of hemostasis, most commonly von Willebrand disease (suspected in young adolescents presenting with heavy menstrual bleeding since menarche).
• O - Ovulatory Dysfunction (AUB-O): Characterized by unpredictable, irregular bleeding without mid-cycle ovulatory symptoms. Chronic anovulation leads to continuous unopposed estrogen stimulation without cyclical progesterone secretion; the endometrium proliferates excessively until it outgrows its vascular supply and breaks down irregularly. Classic causes: Polycystic Ovary Syndrome (PCOS), hypothyroidism, hyperprolactinemia, anorexia, and perimenopause.
• E - Endometrial (AUB-E): Primary localized dysregulation of endometrial hemostatic mechanisms (e.g., deficiency of local vasoconstrictors like endothelin-1 or excess of prostaglandins like $PGE_2$).
• I - Iatrogenic (AUB-I): Unscheduled bleeding secondary to intrauterine devices (copper IUD or LNG-IUD), systemic hormones, psychotropic drugs, or anticoagulants.
• N - Not Otherwise Classified (AUB-N): Rare entities such as arteriovenous malformations or myometrial hypertrophy.

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Polycystic Ovary Syndrome (PCOS)

PCOS (Stein-Leventhal syndrome) is the most common endocrinopathy among reproductive-aged women, affecting 6% to 12% of females.

• Diagnostic Criteria: The Rotterdam Criteria require at least 2 of the following 3 features after excluding secondary causes (such as congenital adrenal hyperplasia, Cushing syndrome, and androgen-secreting tumors):
  1. Oligo- or Anovulation: Infrequent menses ($< 9\text{ cycles/year}$) or amenorrhea.
  2. Hyperandrogenism: Clinical (hirsutism assessed by Ferriman-Gallwey score, severe cystic acne, androgenic alopecia) or biochemical (elevated total/free testosterone, elevated DHEAS).
  3. Polycystic Ovarian Morphology on Ultrasound: Presence of $\ge 20$ follicles per ovary measuring 2 to 9 mm in diameter, or an increased ovarian volume $\ge 10\text{ mL}$ ("string of pearls" appearance).
• Neuroendocrine and Metabolic Pathophysiology:
  • Accelerated GnRH pulsatility drives preferential pituitary LH secretion, leading to an elevated LH:FSH ratio (characteristically $> 2:1$ or $> 3:1$).
  • Excessive LH acts on ovarian theca cells to upregulate CYP17, overproducing androgens (androstenedione and testosterone).
  • Deficient FSH prevents aromatization to estrogen in granulosa cells, arresting follicle maturation.
  • Peripheral conversion of androgens in adipose tissue yields excess Estrone ($E_1$), maintaining chronic anovulation.
  • Insulin Resistance: Peripheral insulin resistance with compensatory hyperinsulinemia is present in up to 80% of patients. Hyperinsulinemia directly stimulates theca cell androgen production and suppresses liver synthesis of Sex Hormone-Binding Globulin (SHBG), dramatically increasing bioavailable free testosterone.
• Long-term Health Risks: Endometrial adenocarcinoma (a 3- to 5-fold increased risk due to continuous, chronic unopposed estrogen driving endometrial hyperplasia without progesterone-induced secretory differentiation and shedding), Type 2 Diabetes Mellitus, Metabolic Syndrome, Non-Alcoholic Fatty Liver Disease (NAFLD), and cardiovascular disease.
• Management:
  • Lifestyle Modification: 5% to 10% weight loss restores ovulatory cycles and improves insulin sensitivity.
  • Combined Oral Contraceptives (COCs): First-line for cycle regulation and hirsutism in patients not desiring pregnancy (suppresses LH, increases hepatic SHBG, reduces free testosterone).
  • Metformin: Enhances insulin sensitivity and reduces hyperandrogenemia.
  • Spironolactone: Anti-androgen competitive aldosterone receptor antagonist; treats persistent hirsutism (teratogenic; requires concurrent contraception).
  • Ovulation Induction for Infertility: Letrozole (aromatase inhibitor) is the first-line agent for ovulation induction in PCOS (demonstrating higher live birth rates than clomiphene citrate).

Puberty

• Usual sequence: thelarche (breast budding, about age 8 to 13), then pubarche (pubic hair), then the growth spurt, then menarche, about 2 to 3 years after thelarche.
• Tanner stages grade breast and pubic hair development.
• Precocious puberty: signs before age 8 in girls.
  • Central (GnRH-dependent) precocious puberty is usually idiopathic in girls and is treated with GnRH agonists.
  • Peripheral precocious puberty has causes such as ovarian tumors, McCune-Albright syndrome, congenital adrenal hyperplasia and exogenous estrogen.
• Delayed puberty: no breast development by age 13.

Abnormal bleeding in adolescents and from drugs or blood disorders

• Immature HPO axis: in the first 1 to 2 years after menarche, cycles are often anovulatory. Unopposed estrogen then causes irregular, sometimes heavy bleeding.
  • Treatment: iron, NSAIDs or tranexamic acid, and cyclic progestins or combined pills.
  • Severe bleeding: high-dose estrogen or combined pills to stabilize the endometrium.
• Blood dyscrasias: von Willebrand disease (the most common inherited bleeding disorder), platelet disorders, leukemia, aplastic anemia and dengue thrombocytopenia.
  • Suspect them with heavy bleeding since menarche, PPH, bleeding after dental extraction or surgery, or a family history.
• Drug-induced bleeding:
  • anticoagulants;
  • antipsychotics and other drugs that raise prolactin;
  • hormonal contraceptives (breakthrough bleeding);
  • tamoxifen (polyps, hyperplasia);
  • herbal estrogens.
• Rule out first: in any reproductive-age woman with abnormal bleeding, exclude pregnancy and pregnancy complications before anything else.

Amenorrhea

• Primary amenorrhea: no menses by 15 years, or by 13 without breast development.

• Secondary amenorrhea: no menses for 3 months in a woman with previously regular cycles, or 6 months if irregular.
  1. Pregnancy test first.
  2. TSH and prolactin.
  3. FSH and estradiol, with a progestin challenge or an assessment of estrogen status.
• Causes of secondary amenorrhea:
  • hypothalamic: stress, weight loss, eating disorders, excessive exercise; low FSH and estrogen; bone loss;
  • hyperprolactinemia: prolactinoma, drugs, hypothyroidism; galactorrhea; treated with cabergoline or bromocriptine;
  • PCOS;
  • primary ovarian insufficiency: loss of ovarian function before 40, high FSH;
  • Sheehan syndrome;
  • Asherman syndrome: intrauterine adhesions after curettage or TB, with a normal hormone profile and no bleeding after an estrogen-progestin challenge.

Dysmenorrhea and premenstrual disorders

• Primary dysmenorrhea:
  • painful menses caused by prostaglandins, without pelvic disease;
  • begins within 1 to 2 years of menarche;
  • treated with NSAIDs started at the onset of pain, or hormonal contraceptives.
• Secondary dysmenorrhea: suggests endometriosis, adenomyosis, fibroids or PID.
• Premenstrual syndrome and premenstrual dysphoric disorder: symptoms in the luteal phase that resolve after menses. Treated with lifestyle measures, SSRIs or combined pills.

Infertility

• Definition: no pregnancy after 12 months of regular unprotected intercourse, or 6 months if the woman is 35 or older.
• Causes:
  • male factor (about a third);
  • ovulatory disorders (PCOS, hypothalamic, thyroid, prolactin);
  • tubal factor (PID, genital TB, endometriosis, previous surgery);
  • uterine factors;
  • unexplained.
• Evaluation:
  • semen analysis;
  • ovulation: menstrual history and mid-luteal progesterone;
  • ovarian reserve: AMH, antral follicle count, day-3 FSH;
  • tubal patency: hysterosalpingography or laparoscopy with dye.
• Treatment:
  • ovulation induction with letrozole (first-line in PCOS) or clomiphene;
  • intrauterine insemination;
  • IVF for tubal disease, severe male factor or failed treatment.
  • Ovarian stimulation risks ovarian hyperstimulation syndrome (enlarged ovaries, ascites, hemoconcentration, thrombosis) and multiple pregnancy.

Menopause, hormone therapy and osteoporosis

• Definition: menopause is 12 months of amenorrhea, at an average age of about 50 to 51.
  • The perimenopause has irregular cycles and rising FSH.
  • Premature menopause occurs before 40.
• Symptoms:
  • vasomotor: hot flushes and night sweats;
  • sleep and mood changes;
  • genitourinary syndrome of menopause: vaginal dryness, dyspareunia, urgency, recurrent UTI;
  • accelerated bone loss and rising cardiovascular risk.
• Hormone therapy (HT):
  • the most effective treatment for vasomotor symptoms;
  • women with a uterus need a progestin with estrogen to prevent endometrial hyperplasia and cancer;
  • benefit is greatest in women under 60 or within 10 years of menopause, at the lowest effective dose, reviewed yearly;
  • contraindications: breast or endometrial cancer, VTE, stroke or coronary disease, active liver disease and unexplained vaginal bleeding;
  • the Women's Health Initiative found more breast cancer, stroke and VTE with combined therapy in older women;
  • vaginal estrogen treats local symptoms with minimal absorption.
• Osteoporosis:
  • diagnosed by DXA T-score of -2.5 or less, or a fragility fracture;
  • prevented with calcium and vitamin D, weight-bearing exercise, no smoking and fall prevention;
  • treated with bisphosphonates: alendronate weekly, taken upright with water on an empty stomach because of esophagitis risk. Rare adverse effects are osteonecrosis of the jaw and atypical femoral fractures.
  • Alternatives include raloxifene (which raises VTE risk), denosumab and teriparatide.