Disorders of the Female Reproductive System¶
Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism · Chapter 404
Key Clinical Points¶
- Anabolic androgenic steroid (AAS) use is detected by a urinary testosterone-to-epitestrogen ratio >6, confirmed by 13C:12C isotope ratio mass spectrometry.
- Treatment of AAS withdrawal hypogonadism involves restoring the HPG axis with clomiphene (50 mg daily) or hCG (1000–2000 IU three times weekly).
- Ovarian germ cell number peaks at mid-gestation (~6–7 million) and decreases precipitously before birth; the pool is nonrenewable.
- The 'two-cell model' of steroidogenesis requires theca cells (LH receptors) to produce androgens and granulosa cells (FSH receptors) to aromatize them into estradiol.
- Precocious puberty in girls is defined as secondary sexual characteristics before age 8 (or <7 for white girls, <6 for black girls).
- Ovulation confirmation: serum progesterone >3 ng/mL (~7 days post-ovulation), basal body temperature increase of 0.24°C, or ultrasound of corpus luteum.
- Anti-müllerian hormone (AMH) is a stable marker of ovarian reserve; it peaks in early twenties and decreases markedly by menopause.
- The dominant follicle is identified by size, granulosa cell proliferation, high FSH receptors, high aromatase activity, and elevated estradiol/inhibin A.
- GnRH neurons migrate from the olfactory placode to the hypothalamus; anosmia with hypogonadotropic hypogonadism suggests lack of olfactory foramina.
- The luteal phase is constant at 12–14 days; variations in cycle length are primarily due to differences in the follicular phase.
DEFINITION & OVERVIEW¶
• Ovarian Function: The ovary orchestrates oocyte release and secretes hormones (estrogen, progesterone, inhibins A/B, relaxin) affecting breast, bone, uterus, and the HPO axis.
• Ovarian Germ Cell Pool: A nonrenewable pool of germ cells is established during gestation. ◦ Primordial germ cells identified by 3rd week of gestation. ◦ Migration to genital ridge complete by 6 weeks. ◦ Transition to oogonial cells; essential for ovarian development. ◦ Pre-natal attrition: At ~8 weeks, oogonias enter prophase of first meiotic division to become primary oocytes. Large population loss occurs before birth (Figure 404-1). ◦ Genetic Note: In 45,X Turner syndrome, germ cells do not persist because survival requires pregranulosa cells dependent on both X chromosomes.
Ovarian Folliculogenesis & Signaling¶
• Follicle Development Stages: ◦ Primordial to Primary: Growth of oocyte; transition from squamous to cuboidal granulosa cells. ◦ Secondary Follicles: Acquisition of zona pellucida; presence of several layers of cuboidal granulosa cells and theca cells. ◦ Signaling Mechanisms: Granulosa cells develop FSH receptors, estradiol production, and androgen receptors. Bidirectional signaling between germ cells and somatic cells is required for maturation. TGF-β family members (GDF-9, BMP-15/GDF-9b) are essential for pregranulosa/pretheca cell migration. Granulosa cell-derived KITL and transcription factor FOXL2 are required for secondary follicle formation. • Premature Ovarian Insufficiency (POI): Mutations in >50 genes (including those affecting follicle development and resistance to loss) are linked to POI or early menopause.
EPIDEMIOLOGY¶
• Puberty Milestones: Menarche is preceded by adrenarche (pubic/axillary hair) due to increased adrenal androgen (DHEA).
• Cycle Dynamics: Standard cycle: ~28 days (range 25–35 days). _Individual variation: ±2 days. _Luteal phase: Constant at 12–14 days; variability in cycle length is driven by the follicular phase. Menstrual bleeding duration: 4–6 days.
• Age-Related Changes: Gradual shortening of cycle length with age (>35 years). _Increase in anovulatory cycles and erratic bleeding as menopause approaches.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Follicle Growth & Selection: ◦ Early growth: Driven by intraovarian factors. ◦ Preovulatory stage: Requires combined FSH and LH stimulation. ◦ Recruitment: Cyclic recruitment of secondary follicles requires FSH. AMH (produced by small preantral follicles) restrains FSH to control the number of follicles entering the growing pool. Dominant follicle selection: Occurs within 5–7 days after menses; most others become atretic. Selection factors: Size, granulosa cell proliferation, high FSH receptors, high aromatase activity, and elevated estradiol/inhibin A (Figure 404-9).
• GnRH Regulation & Development: Origin: GnRH neurons derive from the olfactory placode and neural crest. Migration: Move across the cribriform plate to the hypothalamus. Clinical Correlation: Patients with anosmia and hypogonadotropic hypogonadism often lack olfactory foramina (e.g., bosma arhinia microphthalmia syndrome). Genetic Factors: ANOS1 (KAL1), FGF8/FGFR1, PROK2/PROKR2, NSMF, HS6SD1, and CDH7 are involved in migration. Regulation: KISS1 (Kisspeptin) stimulates GnRH; TAC3 (Neurokinin B) stimulates via kisspeptin signaling; Dyn (Dynorphin) inhibits via kappa opioid receptors.
• Steroidogenesis (Two-Cell Model): Theca Cells: Stimulated by LH; convert cholesterol to androgens (androstenedione, testosterone). Granulosa Cells: Stimulated by FSH; contain aromatase to convert androgens into estrogens (estrone, estradiol). Corpus Luteum: Requires both cell types; luteinized granulosa cells are the main source of progesterone. hCG Role: Binds same receptor as LH; maintains corpus luteum for ~10 weeks post-fertilization.
• Feedback Mechanisms: Negative Feedback: Estradiol, progesterone, and inhibins inhibit FSH/LH secretion. Positive Feedback: High estradiol levels trigger the preovulatory LH surge (Figure 404-8). Inhibin Dynamics: Inhibin B is a marker of granulosa cell proliferation; Inhibin A is produced by the dominant follicle and corpus luteum. AMH Role: Marker of ovarian reserve; inhibits FSH in recruitment of primordial follicles.
CLINICAL FEATURES¶
• Puberty Milestones: Development of secondary sexual characteristics (e.g., breast development, pubic hair). Growth spurt and maturation of the reproductive tract.
DIFFERENTIAL DIAGNOSIS¶
• Precocious Puberty Classification: Central (GnRH Dependent): _Includes idiopathic CNS tumors (astrocytomas, germinomas), hamartomas, infections, and genetic conditions (KISS1, MKRN3). See Table 404-1 for full list of central causes. Peripheral (GnRH Independent): _Includes Congenital Adrenal Hyperplasia (CAH), estrogen-producing tumors, McCune-Albright syndrome, and aromatase excess syndrome. Exogenous exposure to estrogens/androgens or certain oils (lavender, tea-tree)."
DIAGNOSTIC APPROACH¶
• Ovulation Assessment: 1. Serum progesterone: >3 ng/mL measured ~7 days after ovulation. 2. Basal body temperature: Increase of 0.24°C. 3. Ultrasound: Documentation of the corpus luteum.
MANAGEMENT & TREATMENT¶
• AAS Withdrawal Protocol: 1. Identification: Detect usage via urinary testosterone-to-epitestosterone ratio >6. 2. Confirmation: Perform 13C:12C isotope ratio mass spectrometry. 3. Treatment (Restore HPG Axis): Option A: Clomiphene (50 mg daily). Option B: hCG (1000–2000 IU three times weekly).
KEY PEARLS & HIGH-YIELD POINTS¶
• AAS Detection: Ratio >6 is the primary screening threshold. • Luteal Phase: Constant at 12–14 days; variability in cycle length is a follicular phase issue. • Two-Cell Model: Theca (LH) → Androgens; Granulosa (FSH) → Aromatase → Estrogen. • Precocious Puberty: Age cutoffs are 8 (general), 7 (white), and 6 (black). • AMH: Stable marker of ovarian reserve, unlike Inhibin B which fluctuates with the cycle. • GnRH Migration: Lack of olfactory foramina in patients with anosmia and hypogonadotropic hypogonadism indicates a failure of migration from the olfactory placode.
Reference Tables¶
TABLE 404-1 Differential Diagnosis of Precocious Puberty CENTRAL (GnRH DEPENDENT) Idiopathic CNS tumors¶
Harrison's 22e, p.3130
| CENTRAL (GnRH DEPENDENT) | PERIPHERAL (GnRH INDEPENDENT) |
|---|---|
| Idiopathic CNS tumors Hamartomas Astrocytomas Adenomyomas Gliomas Germinomas CNS infection Genetic, i.e., KISS1, KISS1R, MKRN3, DLK1 Head trauma Iatrogenic Radiation Chemotherapy Surgical CNS malformation Arachnoid or suprasellar cysts Septo-optic dysplasia Hydrocephalus |
Congenital adrenal hyperplasia Estrogen-producing tumors Adrenal tumors Ovarian tumors Gonadotropin/hCG-producing tumors Exogenous exposure to estrogen or androgen or lavender or tea-tree oil McCune-Albright syndrome Aromatase excess syndrome |
TABLE 404-2 Evaluation of Precocious and Delayed Puberty Initial Screening Tests History and physical Assessment of…¶
Harrison's 22e, p.3131
| PRECOCIOUS | DELAYED | |
|---|---|---|
| Initial Screening Tests | ||
| History and physical | × | × |
| × | ||
| Bone age | × | × |
| × | ||
| Estradiol, testosterone | × | × |
| × | ||
| 17-Hydroxyprogesterone | × | |
| × | ||
| Complete blood count | × | |
| Electrolytes, renal function | × | |
| IGF-1, IGFBP-3 | × | |
| Secondary Tests | ||
| Pelvic ultrasound | × | × |
| × | ||
| β-hCG | × | |
| × | ||
| ACTH stimulation test | × | |
| × | ||
| Celiac disease panel | × | |
| Karyotype | × |
TABLE 404-3 Differential Diagnosis of Delayed Puberty Hypergonadotropic Ovarian¶
Harrison's 22e, p.3131
- Hypergonadotropic
- Ovarian
- Turner’s syndrome
- Gonadal dysgenesis
- Chemotherapy/radiation therapy
- Galactosemia
- Autoimmune oophoritis
- Congenital lipoid hyperplasia
- Steroidogenic enzyme abnormalities
- 17α-Hydroxylase deficiency
- Aromatase deficiency
- Gonadotropin/receptor mutations
- FSHb, LHR, FSHR
- Androgen resistance syndrome
- Hypogonadotropic
- Genetic
- Hypothalamic syndromes
- Leptin/leptin receptor
- HESX1 (septo-optic dysplasia)
- PC1 (prohormone convertase)
- IHH and Kallmann’s syndrome
- KAL1, FGF8, FGFR1, NSMF, PROK2, PROKR2, SEM3A, HS6ST1, WDR11, CHD7
- KISS1, KISS1R, TAC3, TAC3R, GnRH1, GnRHR, and others
- Abnormalities of pituitary development/function
- PROP1
- CNS tumors/infiltrative disorders
- Craniopharyngioma
- Astrocytoma, germinoma, glioma
- Prolactinomas, other pituitary tumors
- Histiocytosis X
- Chemotherapy/radiation
- Functional
- Chronic diseases
- Malnutrition
- Excessive exercise
- Eating disorders