female repro

Female Reproductive Endocrinology - Dr. Zachow

I. Ovarian Function

  • Female fertility is defined by the ovulation of one mature, viable oocyte during each 28-day reproductive (menstrual) cycle.

  • The menstrual cycle phases:

    • Follicular (Proliferative) Phase: Day 1-14

    • Ovulation: Day 14

    • Luteal (Secretory) Phase: Day 15-28

  • Regulation of ovulation involves:

    • Gonadotropin-releasing hormone (GnRH)

    • Pituitary gonadotropins (LH and FSH)

    • Autocrine and paracrine interactions within the ovary

  • The ovarian-hypothalamic-pituitary axis establishes feedback loops that control female cyclicity and fertility.

A. The Basic Histology

  • The ovary contains functional structures known as follicles that house growing oocytes.

    • Each follicle contains one oocyte and acts as a hormone factory.

    • Follicles produce estrogens, progestins, androgens, protein hormones, growth factors, and cytokines.

  • Two cell populations are found in follicles:

    • Theca Cells:

    • Located around the basal lamina, the outermost layer.

    • Vascularized (theca externa and interna).

    • Granulosa Cells (GC):

    • Inner cell layer surrounding the oocyte, contributing to steroidogenesis.

  • The largest follicles, known as Graafian Follicles, contain a large antrum filled with follicular fluid rich in hormones and growth factors.

B. Neuroendocrine Systems

  • The GnRH pulse-generator in the hypothalamus is influenced by serum steroid hormone concentrations.

    • Pulsatile release of GnRH is necessary for LH and FSH secretion.

    • GnRH Pulse Characteristics:

    • Slow pulses stimulate FSH secretion.

    • Rapid, high amplitude pulses promote LH secretion.

Steroidogenesis Enrichment

  • There are five families of steroid hormones, derived from cholesterol (C27H46O):

    • Progestins

    • Glucocorticoids

    • Mineralocorticoids

    • Androgens

    • Estrogens

  • Cholesterol Structure:

    • 27 carbons, 46 hydrogens, and 1 oxygen.

    • Comprised of 5 hydrocarbon rings (3 hexamers, 1 pentamer) and a 6-carbon side chain.

  • De novo steroidogenesis begins with the CYP11A enzyme complex, which cleaves cholesterol and produces pregnenolone (C21H32O2), a precursor for all steroid hormones.

Examples of Steroidogenic Enzymes

  • 17β-Hydroxysteroid Dehydrogenase (17β HSD): Oxidizes substrates at C17 (e.g., formation of testosterone from androstenedione).

  • 17α-Hydroxylase: Introduces an -OH group at C17 (e.g., forms 17α-hydroxyprogesterone from progesterone).

  • C17,20 Lyase: Cleaves C17-C20 bonds, forming 19-carbon androgens from 21-carbon progestins (e.g., androstenedione from 17α-hydroxyprogesterone).

  • P450 Aromatase (CYP19): Converts androgens into estrogens (e.g., estradiol-17β from testosterone).

B.1. Luteinizing Hormone (LH)

  • Targets theca cells and GC;

    • Stimulates steroidogenesis.

    • Initiates luteinization prior to ovulation.

    • Post-ovulation, promotes progesterone and estrogen production within the corpus luteum.

B.2. Follicle-Stimulating Hormone (FSH)

  • Enables GC to convert androgens into estrogens.

  • Stimulates GC mitosis during follicular growth (folliculogenesis).

  • Works via growth factors, cytokines, and steroid hormones from ovarian cells in response to FSH and/or LH.

  • Signal transduction cascade through cAMP/PKA is crucial for the FSH/LH response.

III. Ovarian Functional Disorders

Hypogonadotrophic Hypogonadism

  • Definition: Insufficient FSH and/or LH leading to suppressed gonadal function.

  • Causes: Lesions in the neuroendocrine system or athletic overtraining.

  • Symptoms: Normal serum gonadotropin levels without cyclical rise; low estradiol levels.

Ovarian Follicles

  • During the follicular phase, a cohort of follicles starts maturing over 3-4 cycles. An anatomical sequence includes:

    • Primordial Follicles: Immature, arrested development with non-steroidogenic GC.

    • Primary Follicles: One layer of cuboidal GC; growing state.

    • Secondary Follicles: Initial steroidogenesis with theca cell appearance.

    • Tertiary (Antral) Follicles: Steroidogenically active, developing antrum.

    • Preovulatory (Graafian) Follicles: Dominant follicle producing androstenedione, testosterone, and estradiol.

    • Corpus Luteum: No oocyte; secretes progesterone and estrogen post-ovulation.

    • Atretic Follicles: Non-selected follicles undergoing apoptosis.

Recruitment and Growth Phases

  • Recruitment involves the differentiation of primordial follicles into primary and secondary follicles.

  • Initial growth phase starts independent of FSH but later requires it; FSH and LH essential for advanced stages.

  • Theca cell differentiation occurs with LH presence, linking growth and vascularization.

Negative Feedback Control

  • Estradiol-17β (E2) production is crucial in feedback loops with FSH and LH, influencing their secretion levels.

Follicular Selection

  • A single follicle is selected to continue maturation while others undergo atresia due to lack of FSH receptors. This process involves:

    • Increased inhibin B production by the selected follicle.

    • The selected follicle maintains growth despite low FSH due to available receptors, while others die from FSH-starvation.

The Basic Model of Follicular Dynamics

  • Selected follicles grow and secrete inhibin B, inducing atresia of non-selected follicles.

  • Theca cells produce androgens while GC convert them into estrogens.

  • FSH and LH promote steroidogenesis and growth, leading to luteinization.

Positive Feedback of Estradiol

  • Rising E2 levels initiate positive feedback loops, increasing FSH and LH, and supporting follicular growth, steroidogenesis, and luteinization.

Gonadotropin Surge and Ovulation

  • The preovulatory gonadotropin surge is triggered by feedback dynamics of E2 and inhibin B.

  • This surge leads to ovulation and marks the pivotal transition in menstrual cycling dynamics.

IV. Ovulation, Luteal Phase, and Menstruation

Ovulation

  • Main Mediator: LH surge, responsible for final oocyte maturation.

  • The oocyte-cumulus complex, enriched with granulosa cells, is extruded from the follicle into the oviduct.

  • Post-ovulation, the follicle becomes a corpus luteum, producing progesterone and E2.

Luteal Phase Dynamics

  • Progesterone, a thermogenic hormone, causes a slight rise in basal body temperature.

  • If fertilization does not occur, LH levels decline, leading to luteolysis (corpus luteum degeneration).

Endometrial Changes and Menstruation

  • The endometrium undergoes cycles driven by E2 and progesterone, preparing for potential implantation.

  • Menstruation results from a sharp decrease in E2 and progesterone levels, causing the shedding of the functional endometrial layer.

V. Applied Physiology: Infertility and Assisted Reproductive Technologies (ART)

  • Infertility Definition: Can't conceive after 1 year (if <35 years old) or 6 months (if >35 years old).

  • Two types:

    • Primary Infertility: Woman has never conceived.

    • Secondary Infertility: Woman has been pregnant before but struggles now.

  • Women can exhibit dysfunctional ovulation or luteal phase defects.

Treatment Strategies

  • Enhanced follicular growth is critical; hormonal manipulation via GnRH agonists/antagonists is common.

  • Clomiphene Citrate: ER antagonist, induces GnRH release and stimulates FSH.

  • Following GnRH suppression protocols, rFSH is administered to promote follicle development and monitored via ultrasound.

  • hCG triggers ovulation for oocyte retrieval in IVF.

VI. Review of Fertilization and Pregnancy

  • Fertilization occurs within the oviduct after ovulation when a sperm binds to the oocyte, initiating meiotic completion.

  • Early embryonic development follows successful fertilization; pregnancy recognition occurs weeks later post-fertilization.

VII. Reproductive Aging

  • Female fertility declines after age 30-35, primarily due to reduced ovarian reserve.

  • Perimenopausal transitions lead to menstrual irregularities.

  • Menopause defined as 12 months without menstruation; characterized by elevated FSH and low E2 levels.

A. Hormone Therapy (HT)

  • HT can alleviate some menopausal symptoms and improve lipid profiles but carries certain risks.

  • Individualized approaches based on patient history and risk assessment recommended for HT administration.

B. Androgen Therapy in Women

  • Ovaries produce less testosterone than testes; however, androgens are crucial for female sexual function.

  • Androgen therapy can restore libido but must be managed carefully to avoid side effects.

VIII. Intro to Reproductive Disorders

Disorders Affecting Reproductive Systems

  • Disorders impacting FSH and LH production can lead to various reproductive issues.

A. Hypothalamic-Pituitary Axis Disorders

  • GnRH secretion disruptions affect gonadotropin levels, thus impeding reproductive viability.

A.1. Polycystic Ovary Syndrome (PCOS)

  • Affects 6-20% of reproductive-age women, characterized by:

    • Irregular menses/anovulation, hyperandrogenemia, and exclusion of other conditions.

  • Management includes lifestyle changes, pharmacologic treatments such as OCPs, clomiphene, and possibly metformin for insulin sensitivity.