Gonadal dysfunction Notes

Chapter 2 Acyanotic Defects NOTES GONADAL DYSFUNCTION GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Disturbance in gonadal development/ function due to gonadal disorder/ hypothalamic-gonadal axis dysfunction CAUSES ▪ Impaired gonadal hormone production due to enzyme deficiency/receptor disturbance/ exogenous hormone use ▪ Hypogonadotropic hypogonadism (AKA central/secondary hypogonadism) ▫ Deficient gonadal hormone production due to decreased gonadotropin production ▫ Gonadotropins, gonadal hormone levels low ▪ Hypergonadotropic hypogonadism (AKA peripheral/primary hypogonadism) ▫ Deficient gonadal hormone production due to disease of gonads ▫ Gonadotropin levels high, gondal hormone levels low RISK FACTORS ▪ Genetic (autosomal dominant disease), history (gestational diabetes) ▪ Environment (e.g. obesity, lack of physical exercise, steroid use) COMPLICATIONS ▪ Most commonly leads to infertility SIGNS & SYMPTOMS ▪ Individuals who are biologically male ▫ Primary sex characteristic dysfunction: small penis, testes; improper testicular descent; low sperm count ▫ Secondary sex characteristic dysfunction: lack of facial, body hair; low muscle mass; failure of voice mutation ▪ Individuals who are biologically female ▫ Primary sex characteristic dysfunction: amenorrhea (absence of menstruation), oligomenorrhea (irregular menstrual cycle) ▫ Secondary sex characteristic dysfunction: lack of breast development, pubic hair DIAGNOSIS LAB RESULTS ▪ Blood tests ▫ Gonadotropic, gonadal hormone levels OTHER DIAGNOSTICS ▪ Tanner scale ▫ Identify delayed development ▫ Development of primary, secondary sex characteristics divided into five stages based on pubic hair, testicular volume, breast development TREATMENT OTHER INTERVENTIONS ▪ Hormone replacement therapy ▪ Infertility treatments OSMOSIS.ORG 93

5-ALPHA-REDUCTASE DEFICIENCY osms.it/5-alpha-reductase_deficiency PATHOLOGY & CAUSES ▪ Autosomal recessive sex-limited genetic mutation in SRD5A2 gene (encodes enzyme 5 alpha reductase) ▪ Defective/absent ▪ Affects only individuals who are biologically male ▪ Defective 5 alpha reductase → ↓ testosterone to dihydrotestosterone conversion → impaired secondary sexual characteristics development COMPLICATIONS ▪ Infertility; inflammation, infection of gonads due to malformation SIGNS & SYMPTOMS Pre-puberty ▪ Male internal sex organs present, external genitalia with female appearance ▫ Phallus doesn’t fully elongate; resembles something between clitoris, penis ▫ Bifid scrotum: scrotum remains split ▫ Hypospadias: urethral opening remains on underside of penis ▫ Ambiguous genitalia: external genitalia does not look clearly male/female Puberty ▪ ↑ testosterone → despite no testosterone conversion, phallus, scrotum grow larger → male appearance, deepening of voice, muscle growth, development of facial, body hair 94 OSMOSIS.ORG DIAGNOSIS LAB RESULTS ▪ Genetic testing ▫ Karyotyping to ensure individual genetically male; confirm enzyme deficiency ▪ Normal serum testosterone level, ↓ dihydrotestosterone levels, ↑ testosterone to dihydrotestosterone ratio OTHER DIAGNOSTICS ▪ Suspected in newborns with ambiguous genitalia TREATMENT MEDICATIONS ▪ Hormone replacement therapy ▫ Male/female sex hormones according to gender role adopted by individual SURGERY ▪ Surgical procedures to help restore external genitalia to nonambiguous appearance OTHER INTERVENTIONS ▪ Assisted reproduction techniques ▫ Internal genitalia do not produce ova, may produce sperm

Chapter 16 Gonadal Dysfunction ANDROGEN INSENSITIVITY SYNDROME osms.it/androgen-insensitivity PATHOLOGY & CAUSES ▪ Genetic disorder of defective androgen receptor gene ▪ Person with XY genotype unresponsive to androgens ▪ Inherited in X-linked recessive pattern TYPES ▪ Complete androgen insensitivity ▫ Completely nonfunctional receptor; cells do not respond to androgens at all ▪ Partial androgen insensitivity ▫ Some remaining function of androgen receptor; cells, tissues partially sensitive to androgens ▪ Mild androgen insensitivity ▫ Masculinization of external genitalia CAUSES ▪ Defect in androgen receptor on external genitalia, genital ducts, testes itself COMPLICATIONS ▪ Infertility (most cases) ▪ Risk of testicular cancer due to cryptorchidism in complete androgen insensitivity SIGNS & SYMPTOMS Complete androgen insensitivity ▪ Cryptorchidism ▫ Without effects of androgens, testes fail to descend into scrotum, remain in abdomen/pelvis ▪ Ineffective spermatogenesis ▫ Epididymis, vas deferens, seminal vesicles do not develop normally ▪ Development of female secondary sex characteristics ▫ Excess testosterone converted into estrogen → breast growth, widening of hips, female fat distribution ▪ Failed development of internal female organs ▫ Testes still produce anti-Müllerian hormone → uterus, fallopian tubes do not develop, vagina ends in blind pouch → female appearance without menstrual cycles Partial androgen insensitivity ▪ Appearance of external genitalia, secondary sex characteristics varies widely Mild androgen insensitivity ▪ Masculinization of external genitalia, some female secondary sex characteristics DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Absence of uterus, ovaries; cryptorchidism LAB RESULTS ▪ ↑ serum testosterone, dihydrotestosterone ▪ Genetic testing ▫ Karyotype; visualize sex chromosomes, ensure individual genetically male OTHER DIAGNOSTICS ▪ Diagnosed in infants with cryptorchidism ▪ Can remain undiagnosed until puberty OSMOSIS.ORG 95

TREATMENT MEDICATIONS ▪ Hormone replacement therapy ▫ Male/female sex hormones according to gender role adopted by individual; testosterone/dihydrotestosterone if male, estrogen if female SURGERY ▪ Surgical removal of testes (esp. in cryptorchidism) to reduce cancer risk ▪ External genitalia correction DELAYED PUBERTY osms.it/delayed-puberty PATHOLOGY & CAUSES ▪ Onset of puberty after age 13 in individuals who are biologically female, after 14 in individuals who are biologically male TYPES Primary/hypergonadotropic hypogonadism ▪ Dysfunction of gonads due to unresponsiveness to luteinizing hormone (LH), follicle-stimulating hormone (FSH)/lack of testosterone/estrogen, progesterone production in gonads → no negative feedback on hypothalamus → overproduction of LH, FSH ▪ Causes of acquired ▫ Radiation therapy, chemotherapy, trauma to gonads ▪ Causes of congenital ▫ Klinefelter syndrome: two X chromosomes in individuals who are biologically male → small testes, sterility ▫ Turner syndrome: X chromosome missing in individuals who are biologically female → dependence on hormonal treatment to develop secondary sex characteristics Secondary/ hypogonadotropic hypogonadism ▪ Hypothalamus/pituitary gland dysfunction; inability to produce gonadotropin-releasing hormone (GnRH)/LH, FSH; suppression 96 OSMOSIS.ORG from other hormones (e.g. prolactin, thyroid hormone) ▪ Causes of acquired ▫ Radiation therapy, chemotherapy, trauma to gonads, tumor of pituitary gland, hypothalamus ▪ Causes of congenital ▫ Kallmann syndrome, panhypopituitarism ▪ General causes ▫ Chronic illness (e.g. cystic fibrosis, celiac disease), excessive exercise, malnutrition/obesity, stress; affect hypothalamus, pituitary release of hormones Constitutional delay ▪ Temporary delay in puberty; doesn’t typically result in infertility ▪ Lack of GnRH, not pathologic → naturally slowed rate of maturation ▪ Onset of puberty occurs naturally, at later age; typically genetic component COMPLICATIONS ▪ Permanent infertility if puberty never begins/fails to complete, sexual maturity never reached SIGNS & SYMPTOMS ▪ Delayed primary, secondary sexual characteristics

Chapter 16 Gonadal Dysfunction DIAGNOSIS LAB RESULTS ▪ Blood hormone levels ▫ Indicate type of hypogonadism; ↓ testosterone, estrogen in low gonad activity; ↓ FSH, LH in suppressed pituitary activity OTHER DIAGNOSTICS TREATMENT MEDICATIONS ▪ Hormone replacement therapy OTHER INTERVENTIONS ▪ Constitutional delay can resolve on own with natural onset of puberty ▪ Infertility treatments ▪ Medical history ▫ Evaluate underlying medical conditions, family history for constitutional delay ▪ Tanner scale ▫ Estimates puberty development KALLMANN SYNDROME osms.it/kallmann-syndrome PATHOLOGY & CAUSES ▪ Type of hypogonadotropic hypogonadism; delayed/absent puberty with impaired sense of smell (anosmia) ▪ Pituitary failure → ↓ sex hormones → hypogonadotropic hypogonadism → failure to start/complete puberty ▪ Defect in migration of neurons from olfactory placode ▫ Olfactory neurons: hyposmia/anosmia (reduced sense of smell) ▫ GnRH neurons: ↓ GnRH → ↓ LH, FSH COMPLICATIONS ▪ Infertility, osteopenia, osteoporosis SIGNS & SYMPTOMS foot, teeth underdevelopment, cleft palate ▪ Neurological sensory, motor ▫ Hearing impairment, colour blindness, dyskinesias, cerebral ataxia DIAGNOSIS LAB RESULTS ▪ Blood hormone levels ▫ ↓ GnRH, LH, FSH, sex hormones ▪ Genetic tests ▫ Gene mutation in FGFR1, PROKR2, PROK2, CHD7, FGF8; associated with Kallmann syndrome OTHER DIAGNOSTICS ▪ Smell test, sperm count ▪ Underdevelopment of primary, secondary sex characteristics; anosmia; long arms in proportion to body (eunuchoid body); osteoporosis; kidney agenesis ▪ Skeletal ▫ Scoliosis, short middle finger, split hand/ OSMOSIS.ORG 97

TREATMENT MEDICATIONS ▪ Hormone therapy ▫ Stimulate puberty, development of secondary sex characteristics ▪ Calcium, vitamin D ▫ Osteopenia OTHER INTERVENTIONS ▪ Infertility treatments POLYCYSTIC OVARY SYNDROME osms.it/polycystic-ovary PATHOLOGY & CAUSES ▪ Excessive androgen production by ovaries; primarily testosterone CAUSES Hyperinsulinemia ▪ Aids LH overproduction ▪ Theca cells in ovary express insulin receptors → excess insulin induces growth, division of theca cells → ↑ LH receptors → hypothalamus ↑ rate of GnRH pulses → ↑ LH secretion Anterior pituitary produces excessive LH ▪ Theca cells produce excess amounts of androstenedione → converted into estrone by aromatase in adipose tissue → negative feedback signal → blocks anterior pituitary from releasing FSH, LH → no LH surge → no dominant follicle to break away from ovary → remains in ovary as cyst/ degenerates with other follicles → no ovulation Excessive adipose tissue ▪ Aromatase in adipose tissue converts androgens to estrogens → ↑ androgens RISK FACTORS ▪ Genetic: autosomal dominant disease ▪ Obesity, lack of physical exercise ▪ History of gestational diabetes 98 OSMOSIS.ORG COMPLICATIONS ▪ Diabetes mellitus, hyperinsulinemia, infertility, increased risk of endometrial cancer SIGNS & SYMPTOMS ▪ High levels of androstenedione → virilization ▫ Excessive hair growth on chin, upper lip, chest, back (hirsutism) ▫ Thinning of hair, from crown of head (male-pattern baldness) ▫ Acne on face, chest, back ▫ Lack of ovulation → oligomenorrhea, amenorrhea → infertility ▪ Insulin resistance ▫ Overweight/obese; dark, velvety patches in creases of neck, groin, underarms (acanthosis nigricans) DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Follicles on one/both ovaries, appear like small cysts LAB RESULTS ▪ Blood tests ▫ ↑ LH to FSH ratio; ↑ androstenedione

Chapter 16 Gonadal Dysfunction TREATMENT MEDICATIONS ▪ Oral contraceptives ▫ Regulate menstrual cycle ▪ Clomiphene citrate ▫ Induce ovulation ▪ Metformin ▫ Increase insulin sensitivity Figure 16.1 An abdominal ultrasound scan demonstrating a polycystic ovary. The cysts are are represented by the well circumscribed hypoechoic areas within the ovary. OTHER DIAGNOSTICS ▪ Rotterdam criteria (2 of 3) ▫ Lack of ovulation, excessive androgens, polycystic ovaries on ultrasound ▪ Oral glucose tolerance test (OGTT) ▫ Establish insulin resistance SURGERY ▪ Ovarian drilling ▫ Puncturing cystic ovary; induces ovulation; can damage ovary, doesn’t resolve overall hormonal imbalance OTHER INTERVENTIONS ▪ Incurable condition, treatment symptoms ▪ Weight loss, low glycemic index diet reduces insulin resistance, improves symptoms PRECOCIOUS PUBERTY osms.it/precocious-puberty PATHOLOGY & CAUSES ▪ Onset of puberty at earlier age than average ▫ ≤ eight in individuals who are biologically female, ≤ nine in individuals who are biologically male TYPES Central/gonadotropin-dependent precocious puberty ▪ Early maturation of hypothalamic-pituitarygonadal axis → early release of LH, FSH → ↑ sex hormones ▪ Cause ▫ Dysfunctional hypothalamus/pituitary gland: tumor releases GnRH/human chorionic gonadotropin (hCG); infection; cyst; radiation damage to brain → impairs negative feedback system in hypothalamic-pituitary-gonadal axis ▫ Idiopathic precocious puberty: most common; normal variation; depends on weight, genetics Peripheral/gonadotropin-independent precocious puberty ▪ Abnormal overproduction of sex hormones by testes/ovaries ▪ Cause ▫ Ovarian/testicular cyst/tumor; genetic conditions (e.g. McCune–Albright syndrome); dysfunction of other glands (thyroid/adrenal gland); exogenous sex hormones from medications, creams OSMOSIS.ORG 99

SIGNS & SYMPTOMS ▪ Child starts progressing through Tanner scale before 95% of other children at same age ▪ Early sexual maturation DIAGNOSIS LAB RESULTS ▪ Gonadotropin hormone levels ▫ Distinguish gonadotropin-dependent/ independent causes OTHER DIAGNOSTICS ▪ Physical exam ▫ Assess growth compared to age; Tanner scale DIAGNOSTIC IMAGING MRI ▪ Structural abnormalities in brain Ultrasound ▪ Screening of gonads X-ray ▪ Estimates bone maturation TREATMENT MEDICATION ▪ Hormone therapy ▫ GnRH analogues → suppress hypothalamic-pituitary-gonadal axis hormones, bind to GnRH receptor on pituitary gland → decrease release of LH, FSH → slow puberty SURGERY ▪ Surgical removal of tumor/cyst from ovaries/ testicles PREMATURE OVARIAN FAILURE osms.it/premature-ovarian-failure PATHOLOGY & CAUSES ▪ AKA primary ovarian insufficiency ▪ Loss of function of ovaries before age 40; not caused by menopause ▪ Follicles stop responding to pituitary LH, FSH → disrupted ovulation → ↓ estrogen, progesterone, androstenedione → amenorrhea, hypogonadotropism, hypoestrogenism ▪ Around half of biologically-female individuals maintain some intermittent ovarian function ▪ Usually no clear cause; associated with ▫ Acquired: chemotherapy, radiotherapy, autoimmune destruction ▫ Genetic: Turner syndrome, fragile X syndrome, BRCA1 mutations → 100 OSMOSIS.ORG gonadal dysgenesis ▪ Two mechanisms ▫ No remaining follicles: ovary started off with few/rapid degeneration ▫ Follicles dysfunctional: hypergonadotropic hypogonadism; estrogen-low pituitary increases LH, FSH production COMPLICATIONS ▪ Infertility, cardiovascular disease, osteoporosis, hypothyroidism, Addison’s disease

Chapter 16 Gonadal Dysfunction SIGNS & SYMPTOMS ▪ Absence of ovulation; low levels of estrogen, progesterone ▪ Normal puberty with regular periods before disorder develops ▪ Infrequent menstrual periods → difficulty conceiving/infertility ▪ Lack of hormones: hot flashes, night sweats, vaginal dryness → dyspareunia (pain during sex) ▪ ↓ estrogen: cardiovascular disease, osteoporosis, decreased bone density ▪ Symptoms mimic natural menopause; some biologically-female individuals still able to get pregnant due to intermittent ovarian function DIAGNOSIS LAB RESULTS ▪ ↓ ovarian hormones (estrogen), ↑ LH, FSH ▪ If autoimmune cause suspected ▫ Test for steroid cell antibodies/ sulfoxythiocarbamate alkynes (STCAs) ▪ Genetic testing ▫ Karyotype, chromosomal abnormalities; evaluate for genetic disease TREATMENT MEDICATIONS ▪ Hormone replacement therapy ▫ Estrogen, progesterone OTHER INTERVENTIONS ▪ In-vitro fertilization ▫ Treat infertility DIAGNOSTIC IMAGING Ultrasound ▪ Shrunken ovaries OSMOSIS.ORG 101