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Faculty of Medicine Practical Activity - Pathophysiology, Year III Medicine, Module III Pathology of the Female Reproductive System

The Female Reproductive System

The female reproductive system has several vital roles:

  • Production of female gametes (oocytes)

  • Secretion of female sex hormones, specifically estrogen and progesterone

  • Facilitation of fertilization, gestation, and birth

  • The normal functioning of this system is closely linked to the menstrual cycle.

The menstrual cycle encompasses a series of cyclical, hormonal, and morphofunctional changes occurring in the following:

  • Hypothalamic-pituitary-ovarian axis

  • Ovaries

  • Endometrium

The overall purpose of the menstrual cycle is to prepare the female body for a potential pregnancy.

Menstrual Cycle - General Characteristics

Key Features

  • Normal Duration: 21–35 days

  • Onset: Menarche

  • Cessation: Menopause

  • Regulation: This cycle is controlled through the interaction of multiple hormones: GnRH (Gonadotropin-releasing hormone), FSH (Follicle-stimulating hormone), LH (Luteinizing hormone), alongside estrogen and progesterone.

Phases of the Menstrual Cycle

  1. Follicular Phase: Dominated by estrogen; ovarian follicles mature.

  2. Ovulation: The release of the mature egg occurs.

  3. Luteal Phase: Dominated by progesterone; endometrial preparation for implantation.

  4. Menstruation: Elimination of the endometrium following the absence of pregnancy.

Menstrual Cycle Disorders

Overview

Menstrual cycle disorders reflect dysfunctions that may be hormonal, ovarian, or genetic in nature, presenting as pathological changes in:

  • Absence of menstruation

  • Duration of menstruation and menstrual cycle

  • Regularity of cycles

  • Volume of blood loss during menstruation

Classification of Menstrual Cycle Disorders

  1. Amenorrhea: Absence of menstruation in women of reproductive age.
       - Primary Amenorrhea: Absence of menstruation until age 16, in the presence of secondary sexual characteristics; or absence of both until age 13.
       - Etiologies: Hypothalamic or pituitary dysfunction, anatomical abnormalities (e.g., absence of the uterus, vaginal septum), chromosomal abnormalities leading to gonadal dysgenesis.

  2. Oligomenorrhea: Infrequent menstruation; cycles longer than 35 days.

  3. Polymenorrhea: Frequent menstrual cycles; cycles shorter than 21 days.

  4. Menorrhagia: Heavy menstrual bleeding lasting more than 7 days, with blood loss exceeding 100ml.

  5. Metrorrhagia: Irregular bleeding that occurs outside the menstrual period.

Amenorrhea

Descriptions

  • Primary Amenorrhea: Defined as the complete absence of menstruation alongside secondary sexual characteristics after age 16, or the absence of both by age 13.
        - Etiology: Conditions such as hypothalamic or pituitary dysfunction, anatomical abnormalities like absence of the uterus, chromosomal anomalies, etc.

  • Secondary Amenorrhea: Defined as the absence of menstruation for 6 months or more following prior menstrual cycles.
        - Etiology: Causes include pregnancy, ovarian failure, hypothalamic or pituitary disorders, uterine anomalies, polycystic ovary syndrome (PCOS), anorexia nervosa, nutritional deficiencies, thyroid disorders, and medication effects.
        - Notably due to primary ovarian insufficiency leading to hypergonadotropic hypogonadism when function ceases before age 40.

Gonadal Dysgenesis

Definitions

  • Gonadal dysgenesis is characterized by incomplete or absent development of the gonads, resulting from defects in embryonic differentiation, which results in primary gonadal insufficiency, hypergonadotropic hypogonadism, and sexual development disorders.
      - In females, this condition leads to fibrous ovarian replacements ("band ovaries") that lack functional follicles, resulting in primary amenorrhea, absence of spontaneous puberty, and infertility.
      - Common gonosomal trisomies include XXV, XYY, and X. Monosomy X (characteristic of Turner syndrome) is defined by the absence of one X chromosome, typically resulting in a karyotype of 45,X, which has a prevalence of 1 in 2,500 female newborns.
      - Delayed puberty is marked by the absence of secondary sexual characteristics after age 14 which may arise from central defects or gonadal dysfunction such as in Turner syndrome and XX gonadal dysgenesis.

Etiology of Gonadal Dysgenesis

  1. Genetic Causes (Most Common):
       - Chromosomal Abnormalities:
         - X Monosomy (45,X) associated with Turner syndrome.
         - Chromosomal mosaicism (45,X/46,XX).
         - Structural abnormalities of the X chromosome involving genetic defects influencing gonadal development.

  2. Embryonic Causes:
       - Disorders of primordial germ cell migration and defects in genital ridge differentiation.

  3. Acquired Causes (Rare):
       - Gonadal damage resulting from radiotherapy or chemotherapy, as well as autoimmune processes destroying gonadal tissue.

Turner Syndrome

Definition and Etiology

  • Turner syndrome is known as a common cause of premature ovarian failure, leading to delayed puberty and primary amenorrhea.

  • Some individuals may have menarche and menstrual cycles due to mosaicism and have an escalated risk for premature ovarian failure.

  • It is a genetic chromosomal disorder characterized by complete or partial absence of an X chromosome, predominantly resulting in an abnormal karyotype (most commonly 45,X) affecting somatic and sexual development in females, with an incidence of 1 in 2,500.

  • Associated Conditions:
       - Gonadal dysgenesis
       - Primary ovarian failure
       - Hypergonadotropic hypogonadism
       - Primary amenorrhea and infertility.

Risk Factors

  1. Maternal/Periconceptional Factors:
       - Advanced maternal age.
       - Errors of meiotic nondisjunction in parental gametes, notably more frequently paternal.
       - Early postzygotic mitotic events leading to loss of the X chromosome.

  2. Potential Environmental Factors:
       - Exposure of parents to ionizing radiation and mutagenic chemicals.
       - Maternal viral infections during the first trimester.

  3. Other Considerations:
       - The majority of occurrences are sporadic, with little family history.
       - The risk of recurrence remains very low.
       - No definitive correlations to maternal lifestyle factors such as smoking or alcohol consumption.

Pathophysiological Mechanisms

  1. Primary Genetic Anomaly:
       - Presence of total or partial absence of an X chromosome (i.e., 45,X or 45,X/46,XX).

  2. Impaired Gonadal Development:
       - Incomplete germ cell migration leading to premature oocyte apoptosis; ovaries fail to differentiate normally.

  3. Gonadal Dysgenesis:
       - Ovaries are small, fibrotic, lacking functional follicles, and resemble band-like structures.

  4. Primary Ovarian Failure:
       - Lack of estrogen and progesterone production leads to the inability of the ovaries to initiate puberty and menstrual cycles.

  5. Hormonal Imbalance:
       - Decreased estrogen leads to loss of negative feedback on hypothalamus and pituitary, resulting in elevated levels of FSH and LH, marking hypergonadotropic hypogonadism.

  6. Hypothalamic–Pituitary–Ovarian Axis Dysfunction:
       - Although this axis functions, the gonads do not respond to gonadotropic stimulation, leading to absence of ovulation and cyclic ovarian activity.

Clinical Picture

  1. General Manifestations:
       - Short stature due to postnatal growth deficit.
       - Short neck with lateral folds (pterygium colli).
       - Broad “shield-shaped” chest and widely spaced nipples.
       - Other anatomical features include cubitus valgus and congenital edema of hands and feet at birth, ogival palate, low-set ears.
       - Increased incidence of autoimmune diseases (2%), structural heart anomalies (e.g. bicuspid aortic valves), aortic coarctation and dissection, coronary artery disease, high blood pressure, type 2 diabetes, horseshoe kidney, lymphedema, low bone density, and hearing problems.
       - Additionally, there is a link to inflammatory bowel disease.

  2. Gonadal and Sexual Manifestations:
       - Features include gonadal dysgenesis (band ovaries), primary ovarian failure, lack of spontaneous puberty, and underdevelopment of secondary sexual features like insufficient breast development and reduced pubic hair.
       - This results in primary amenorrhea and infertility.

Diagnosis

  1. Hormonal Tests:
       - Elevated FSH and LH levels, along with decreased estradiol indicate hypergonadotropic hypogonadism.
       - Recording the exclusion of other amenorrhea causes through TSH, Prolactin, and β-Hcg testing prior to genetic confirmation is critical.
       

  2. Genetic Testing:
       - Genetic analysis offering definitive diagnosis through karyotyping from peripheral blood or other cell cultures.
       

  3. Associated Imaging Investigations:
       - Pelvic ultrasound, echocardiography, and renal ultrasound.
       

  4. Tests for Associated Complications:
       - TSH, antithyroid antibodies, blood glucose, HbA1c, lipid profile, bone densitometry (DEXA).

Polycystic Ovary Syndrome (PCOS)

Definitions

Polycystic ovary syndrome (PCOS), also known as Stein–Leventhal syndrome, is recognized as a common endocrine-metabolic disorder characterized by the dysfunction of the hypothalamic–pituitary–ovarian axis, with primary features including:

  • Hyperandrogenism

  • Chronic anovulation or oligoovulation

  • Microcystic ovaries

PCOS stands as the leading cause of hyperandrogenism in women and a significant cause of infertility, impacting approximately 5–7% of women of reproductive age.

Hyperandrogenism is a pathological state characterized by elevated androgen levels (including testosterone, androstenedione, DHEA) in women, often occurring due to increased ovarian and/or adrenal production or heightened sensitivity to androgens.

Etiology

  1. Genetic/Familial Predisposition:
       - Demonstrated through polygenic inheritance involving genes such as CYP17A1, CYP11A1, LHCGR, FSHR, INSR, DENND1A, and SHBG.

  2. Ovarian Endocrine Factors:
       - Associated with ovarian androgen hypersecretion.

  3. Adrenal Factors:
       - Involving adrenal androgen overproduction (e.g., elevated DHEA).

  4. Metabolic Factors:
       - Presence of insulin resistance with or without hyperinsulinism.

  5. Obesity:
       - Identified as an aggravating or contributing factor.

  6. Environmental and Lifestyle Factors:
       - Factors such as high-calorie diets, sedentary behaviors, and stress are also considered contributory.

Pathophysiological Mechanisms

  1. Primary Functional Abnormality:
       - Functional abnormality noted in the hypothalamic–pituitary–ovarian axis, characterized by hyperandrogenism. Increased LH levels are more of a consequence than the initial cause of ovarian dysfunction.

  2. Hyperproduction of Androgens:
       - Increased ovarian androgen production is often linked with adrenal androgen hypersecretion. This may stem from abnormal function of the enzyme CYP17A1, which plays a key role in androgen biosynthesis in both ovaries and adrenal glands.

  3. Local Ovarian Effects of Hyperandrogenism:
       - This includes premature follicular atresia and an accumulation of immature follicles, with multiple cysts formation leading to oligoovulation or chronic anovulation.

  4. Progesterone Deficiency:
       - The absence of ovulation leads to no corpus luteum formation and thus reduced progesterone secretion. This exposes the endometrium to unopposed estrogen stimulation, elevating the risk of endometrial cancer.

  5. Peripheral Conversion of Androgens:
       - Excess androgens convert to estrogens in peripheral adipose tissue, a process intensified by obesity, leading to irregular estrogen secretion and chronic estrogen stimulation without corresponding progesterone.

  6. Disruption of Pituitary Secretion:
       - Estrogens produced peripherally alongside progesterone deficiency results in elevated LH secretion, maintaining an increased LH/FSH ratio. The physiological LH peak needed for ovulation becomes absent.

Insulin Resistance Mechanism

Women diagnosed with PCOS exhibit disproportionate peripheral insulin resistance relative to their obesity levels. Mechanisms include:

  • Defects in insulin receptors and post-receptor defects (e.g., decreased glucose transporter expression) leading to compensatory hyperinsulinemia.

This excess insulin has dual roles:

  • It stimulates ovarian androgen production directly.

  • It increases pituitary secretion of LH.

This cycle fosters a vicious pattern: hyperandrogenism leads to anovulation, and in turn, generates further hyperinsulinemia.

Clinical Picture

  1. Menstrual Disorders:
       - Oligomenorrhea, secondary amenorrhea, and irregular menstrual cycles due to chronic anovulation.

  2. Manifestations of Hyperandrogenism:
       - Including hirsutism following male-pattern hair distribution, persistent acne, and androgenic alopecia.

  3. Ovarian Manifestations:
       - Enlarged ovaries reveal microcystic appearances under ultrasound, demonstrating multiple subcapsular cysts and hypertrophied ovarian stroma.

  4. Infertility:
       - Resulting from lack of ovulation.

  5. Metabolic Manifestations:
       - These encompass obesity (especially abdominal), insulin resistance, hyperinsulinemia, and an increased likelihood of type 2 diabetes, metabolic syndrome, and dyslipidemia.

  6. Associated Endocrine Manifestations:
       - Include irregularities often noted in endocrine assessments.

  7. Dermatological Manifestations:
       - Such as seborrhea and acanthosis nigricans (a marker of insulin resistance) alongside common skin oiliness.

  8. Psychological Manifestations:
       - Conditions like anxiety, depression, and body image disorders may emerge.

  9. Long-term Complications:
       - Notable risks include endometrial hyperplasia, heightened chances of endometrial cancer, cardiovascular ailments, and persistent infertility.

Positive Diagnosis - Rotterdam Criteria

The diagnosis for PCOS is affirmed when at least two of three criteria are met, following the exclusion of other disorders:

  1. Oligoovulation or Anovulation:
       - Presentations like oligomenorrhea, secondary amenorrhea, and irregular menstrual cycles.

  2. Hyperandrogenism:
       - Clinically manifested as hirsutism, acne, androgenic alopecia, or biologically as increased serum androgens (total/free testosterone, androstenedione, DHEA).

  3. Polycystic Ovaries on Ultrasound:
       - Presentation of ≥12 follicles per ovary (2–9 mm) or an ovarian volume exceeding 10 cm³, notable for subcapsular follicle arrangements referred to as a "string of pearls".

Positive Diagnosis Procedures

  1. Clinical Evaluation:
       - History of menstrual cycles, hairiness evaluations via the Ferriman–Gallwey score, assessment of BMI and fat distribution, and signs indicating insulin resistance such as acanthosis nigricans.

  2. Hormonal Investigations:
       - Involves testing LH, FSH (noticing elevated LH/FSH ratios), total and free testosterone levels, DHEA-S, SHBG, and progesterone for ovulation assessments.

  3. Transvaginal Ultrasound:
       - Micropolycystic ovarian appearances, increased ovarian volume, and absence of dominant follicles are key aspects.

  4. Exclusion of Other Causes:
       - Must rule out conditions such as congenital adrenal hyperplasia, androgen-secreting tumors, Cushing's syndrome, hyperprolactinemia, and thyroid disorders.

Treatment

  1. General Measures (First Line of Treatment):
       - Weight loss (5–10% of body weight), balanced diet, and regular physical activity are fundamental in reducing insulin resistance and improving hormonal balance.
       - Increased muscle tissue enhances insulin-mediated glucose uptake, thus improving tissue sensitivity to insulin, reducing hyperinsulinemia, resulting in less ovarian stimulation for androgen production and potentially restoring ovulation.

  2. Management of Menstrual Disorders and Hyperandrogenism:
       - Combined Oral Contraceptives (COC) and antiandrogens (to be used only alongside contraception due to teratogenic risks).

  3. Insulin Resistance Treatment:
       - Metformin is especially beneficial in obese patients or those with glucose intolerance or diabetes.

  4. Infertility Treatment:
       - Ovulation induction options include Letrozole, used as first-line therapy, with Clomiphene citrate as an alternative.

  5. Management of Long-term Complications:
       - Includes prevention of endometrial hyperplasia and monitoring for metabolic and cardiovascular risks.