Disorders of theTestes and Male Reproductive System¶

Chapter 403 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism · Chapter 403

Key Clinical Points¶

Infertility affects approximately 5% of men; increasingly treatable via hormone replacement or sperm transfer techniques.
Testicular volume is the first clinical sign of puberty, reflecting an increase in seminiferous tubule volume; growth spurt occurs at a testicular volume of ~10–12 mL.
Total testosterone (T) range for nonobese men (19–39 years): 264–916 ng/dL (LC-MS/MS).
WHO semen parameters: Volume ≥ 1.5 mL, total sperm ≥ 39 million, concentration ≥ 15 million/mL, vitality ≥ 58%, progressive motility ≥ 32%, total motility ≥ 40%, normal forms ≥ 4.0%.
Y chromosome microdeletions (AZFa, AZFb, AZFbc, and AZFc) are associated with oligospermia or azoospermia; AZFc deletions are most common in infertile men.
Secondary hypogonadism is highly amenable to treatment with pulsatile GnRH or gonadotropins.
A normal biopsy in an azoospermic man with a normal FSH level suggests obstruction of the vas deferens, which may be correctable surgically.
SHBG concentrations are decreased by androgens, obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome, and genetic factors.
Precocious puberty in boys: progressive testicular enlargement (>4 mL) before 9 years of age associated with acceleration of linear growth and bone age.
Finasteride predominantly inhibits SRD5A2; dutasteride is a dual inhibitor of both SRD5A1 and SRD5A2.

DEFINITION & OVERVIEW¶

• Core Function: Regulates sex differentiation, androgenization, and the hormonal changes accompanying puberty, leading to spermatogenesis and fertility. • Key Cellular Components: ◦ Leydig cells: Produce testosterone under LH control; essential for sperm production and development of secondary sex characteristics. ◦ Sertoli cells: "Nurse" germ cells; required for differentiation/maturation into sperm; produce inhibin B (selectively suppresses pituitary FSH). • Developmental Milestones: ◦ Fetal stage: Testosterone and DHT induce Wolffian duct development (epididymis, vas deferens, seminal vesicles) and virilization of external genitalia. ◦ Sertoli cells: Produce Müllerian inhibiting substance (MIS), causing regression of fallopian tubes, uterus, and upper vagina. ◦ Testicular descent: Mediated by Leydig cell production of insulin-like factor 3 (INSL3) acting on RXFP2, and testosterone acting on the androgen receptor (AR).

EPIDEMIOLOGY¶

• Infertility: Affects ~5% of men; increasingly treatable via hormone replacement or sperm transfer. • Puberty Trends: Age of onset has fallen by 3 years over the last century, linked to improved nutrition and rising obesity rates.

ETIOLOGY & PATHOPHYSIOLOGY¶

Hypothalamic-Pituitary-Testis Axis¶

• GnRH Regulation: Pulsatile secretion controlled by KNDy neurons (Kisspeptin, Neurokinin B, Dynorphin). ◦ Kisspeptin: Binds to GPR54; essential for puberty (mutations lead to failure of puberty). ◦ Neurokinin B (NKB): Activates NK3R to stimulate kisspeptin release. ◦ Dynorphin (DYN): Inhibits kisspeptin via K-type 2 opioid receptor. • Feedback Loop: Testosterone, estradiol, and progesterone provide negative feedback on KNDy neurons. • Gonadotropin Action: ◦ LH: Acts on Leydig cells to stimulate testosterone synthesis. ◦ FSH: Acts on Sertoli cells to regulate spermatogenesis and inhibin B production.

Leydig Cell & Androgen Synthesis¶

• Rate-Limiting Step: Transport of cholesterol to the inner mitochondrial membrane via StAR protein and TSPO (formerly peripheral benzodiazepine receptor protein). ◦ StAR mutations → Congenital lipoid adrenal hyperplasia (low androgen/steroids). • Enzymatic Pathway: ◦ CYP17A1: Catalyzes conversion of progesterone to 17α-hydroxyprogesterone; possesses 17,20-lyase activity in testis and zona reticularis. ◦ 5α-reductase (SRD5A1, SRD5A2): Converts testosterone to DHT. Most mutations occur in SRD5A2. ◦ Aromatase (CYP19): Converts testosterone/androstenedione to estradiol. • Drug Actions: ◦ Finasteride: Inhibits SRD5A2. ◦ Dutasteride: Dual inhibitor of both SRD5A1 and SRD5A2.

Testosterone Metabolism & Action¶

• Circulation: 95% of testosterone is from testicular production; 0.5 mg/d from adrenal/peripheral conversion. ◦ DHT: Essential for masculinization of external genitalia, prostate growth, and hair growth. ◦ Estradiol: Required for bone resorption, epiphyseal closure, and libido. • Backdoor Pathway: 17α-hydroxyprogesterone → androsterone → DHT (active in human fetal testis). • Metabolic Products: ◦ 5α-androstane-3β,17β-diol: High-affinity ligand/agonist of estrogen receptor β. ◦ 5α-androstane-3α,17β-diol: Modulator of GABA receptors. ◦ 11-oxygenated steroids (11-ketotestosterone, 11-ketoandrostenedione): Potent androgens produced in testes/adrenals.

Spermatogenesis¶

• Seminiferous Tubules: Contain the germ cells; blood-testist barrier formed by Sertoli cell tight junctions. ◦ Spermatogonia: Stem cells for self-renewal. ◦ Spermiogenesis: Differentiation into mature sperm. • Hormonal Requirements: ◦ FSH & Testosterone: Required for progression of meiosis and spermiation. ◦ Inhibin B: Produced by Sertoli cells; inhibits FSH.

Y Chromosome & Microdeletions¶

• Structure: Contains MSY (Male-Specific Region) with 91% homology to X chromosome. ◦ AZF Regions: 1. AZFa, AZFb: Associated with Sertoli cell issues and azoospermia; poor prognosis for sperm retrieval. 2. AZFc: Most common in infertile men; associated with oligozoospermia; higher success for sperm retrieval.

CLINICAL FEATURES¶

General Presentation¶

• History: Focus on puberty, linear growth, morning erections, and libido. ◦ Note: Young hypogonadal men may still achieve erection with visual stimuli. • Physical Exam: ◦ Secondary Sex Characteristics: Hair growth (face, axilla, chest, pubic), gynecomastia, testicular volume. ◦ Testicular Volume: 12–25 mL (Normal); 1–2 mL in Klinefelter syndrome. ◦ Eunuchoid Proportions: Arm span >2 cm greater than height (indicates pre-pubertal androgen deficiency).

Precocious Puberty¶

• Definition: Progressive testicular enlargement (>4 mL) before age 9, with accelerated growth/bone age. ◦ Table 403-1 Causes: 1. Gonadotropin-dependent: Idiopathic; CNS tumors (e.g., hypothalamic hamartoma, optic glioma); mutations in KISS1, KISS1R, or MKRN3. 2. Gonadotropin-independent: Congenital adrenal hyperplasia (CAH); hCG-secreting tumor; McCune-Albright syndrome; Activating LH receptor mutations; Exogenous androgens; Androgen-producing tumors of the adrenal or testis.

DIAGNOSTIC APPROACH¶

Initial Screening: Measure total testosterone (T) in a fasting, early morning sample.
Interpretation of T Levels: ◦ >350 ng/dL → Normal; evaluate other causes of symptoms. ◦ 200–350 ng/dL → Borderline; repeat total and free T. ◦ If repeated results are normal → Evaluate other causes. ◦ If repeated results are low → Proceed to step 3. ◦ <200 ng/dL → Low; proceed to step 3.
Gonadotropin Assessment (if T is confirmed low): Measure LH and FSH.
Differentiation of Site: ◦ Low T + Low or Inappropriately Normal LH → Hypogonadotropic (Pituitary/Systemic workup: Prolactin, Ferritin, MRI). ◦ Low T + High LH → Hypergonadotropic (Testicular dysfunction; Karyotype for Klinefelter).

MANAGEMENT & TREATMENT¶

Male Factor Infertility¶

• Azoospermia with Normal FSH: Suggests obstruction of the vas deferens; may be surgically correctable.

Secondary Hypogonadism Treatment¶

Hormone Replacement: Use testosterone formulations based on patient preference.
Formulation Selection (Table 403-3): ◦ T enanthate/cypionate: 140–200 mg IM every 2 weeks or 70–100 mg/wk; provides steady levels but has 'peaks and valleys'. ◦ Transdermal Gels: Convenient, good skin tolerability; higher DHT:T ratio in hypogonadal men. ◦ T Pellets: Subcutaneous implantation; sustained levels for 3–4 months; requires surgical insertion. ◦ Oral TU (Undecanoate): Self-emulsifying system; convenient; high DHT:T ratio. ◦ Injectable long-acting TU: Infrequent administration; risk of POME (Pulmonary Oil Microembolism) reaction (monitor for 30 min post-injection). ◦ Intranasal T: 11 mg bid; avoids some systemic side effects; monitor for nasal irritation.
Monitoring Protocol (Table 403-5): ◦ Frequency: Evaluate 3–6 months after initiation, then annually. ◦ Target Range: Aim for mid-normal range (~400–750 ng/dL). ◦ Hematocrit: Check at baseline and every 3–6 months; if >54%, stop therapy until safe; evaluate for hypoxia and sleep apnea. ◦ Prostate Screening (Age ≥ 55): Baseline PSA, then 3–6 months, then annually. ◦ Urologic Consultation Required If: ◦ PSA increase >1.4 ng/mL in first 12 months. ◦ PSA >4 ng/mL at any time. ◦ Prostatic abnormality on DRE or severe LUTS.

PROGNOSIS & COMPLICATIONS¶

• POME Reaction: Risk with large-volume injectable TU; symptoms include cough, dyspnea, chest pain, and syncope. Management: Monitor for 30 min post-injection. ◦ Testosterone Side Effects: Potential for increased PSA, erythrocytosis (Hct >50%), and risk of cardiovascular events in high-risk patients.

SPECIAL CONSIDERATIONS¶

• Klinefelter Syndrome: Characterized by markedly reduced testicular volumes (1–2 mL). ◦ Gynecomastia Workup (Flowchart 2): 1. Identify if tissue is [Adipose] or [Glandular]. 2. If Adipose: Mammography/imaging; follow with serial exams. 3. If Glandular and 'Stable' (e.g., <4cm, known cause): Follow with serial exams. 4. If Glandular and 'Unstable' (≥ 4cm, no clear cause, T-deficiency signs): Lab workup. ◦ Low T, high E2:T → T deficiency syndrome. ◦ High E2, normal/low T, high E2:T → Ultrasound of testes (rule out E2-producing tumor). ◦ High hCGβ → Ultrasound of testes/adrenal/chest (locate hCG-producing tumor). ◦ Very high SHBG, normal/high T, normal E2 → Measure free T and E2. ◦ Sperm Retrieval: AZFc deletions are most common in infertile men; others (AZFa, AZFb) associated with poor prognosis for sperm retrieval.

KEY PEARLS & CLINICAL TRAPS¶

• Testosterone Levels: Use fasting, early morning samples. <200 ng/dL is the threshold for low testosterone. ◦ Safety Precautions (Table 403-4): 1. High Risk: Metastatic prostate cancer, some breast cancers, Thrombophilia. 2. Moderate/High Risk (Caution): Undiagnosed prostate nodule or induration; PSA >3; Eryrocytosis (Hct >50%); Severe LUTS with BPH (AUA score >19); Uncontrolled heart failure; MI, stroke, or ACS in preceding 4 months. ◦ Sperm Parameters: Use WHO criteria (Volume ≥ 1.5 mL, Total ≥ 39 million, Conc ≥ 15 million/mL, Vitality ≥ 58%, Prog. Motility ≥ 32%, Total Motility ≥ 40%, Normal Forms ≥ 4.0%). ◦ Sperm Retrieval: AZFc deletions are most common in infertile men.

Flowcharts & Algorithms¶

Flowchart 1: Biochemical Pathway of Sterol Conversion
Pathway A (Classical): 5α-dihydrotestosterone → [Classical Pathway] → Estradiol.
Pathway B (Backdoor): 5α-dihydrotestosterone $xr→{ ext{HSD17B6, AKR1C2}} Androstanediol →$ Estradiol.
Flowchart 2: Evaluation of Gynecomastia
Step 1: Identify tissue type (Adipose vs. Glandular).
Step 2 (If Adipose): Mammography/imaging → Follow with serial exams.
Step 3 (If Glandular): Assess for 'Stable' criteria (e.g., size <4cm, known cause, etc.).
If Yes: Follow with serial exams.
If No (Glandular ≥ 4cm, no clear cause, T-deficiency signs): Lab Workup (T, SHBG, LH, FSH, E2, TSH, hCG).
Result A (Low T, high E2:T): T deficiency syndrome.
Result B (High E2, normal/low T, high E2:T): Ultrasound of testes (rule out E2-producing tumor).
Result C (High hCGβ): Ultrasound of testes/adrenal/chest (locate hCG-producing tumor).
Result D (Very high SHBG, normal T, normal E2): Measure free T and E2.
Flowchart 3: Evaluation of Hypogonadism
Step 1: Measure fasting/early morning total T.
350 ng/dL: Normal → Evaluate other causes; follow if indicated.
200–350 ng/dL: Borderline → Repeat total and free T.
If Total/Free T normal → Evaluate other causes.
If Total/free T low → Measure LH and FSH.
<200 ng/dL: Low → Measure LH and FSH.
Step 2 (If T is confirmed low):
LH low or inappropriately normal → Hypogonadotropic Workup (Rule out systemic illness; measure prolactin, ferritin; evaluate other pituitary hormones; MRI).
LH high → Hypergonadotropic Workup (Primary testicular dysfunction; Karyotype to exclude Klinefelter).

Reference Tables¶

TABLE 403-1 Causes of Precocious or Delayed Puberty in Boys I. Precocious puberty¶

Harrison's 22e, p.3109

I. Precocious puberty
A. Gonadotropin-dependent
1. Idiopathic
2. CNS tumors such as hypothalamic hamartoma, optic glioma, arachnoid
cysts, astrocytoma, ependymoma, or tunerous sclerosis
3. Inflammatory and infectious lesions
4. Mutations in genes that regulate GnRH secretion, such as kisspeptin
(KISS1), kisspeptin receptor (KISS1R), and makorin ring finger protein
3 (MKRN3)
B. Gonadotropin-independent
1. Congenital adrenal hyperplasia
2. hCG-secreting tumor
3. McCune-Albright syndrome
4. Activating LH receptor mutations (familial male-limited precocious
puberty)
5. Exogenous androgens
6. Androgen producing tumors of the adrenal or the testis
II. Delayed puberty
A. Constitutional delay of growth and puberty
B. Systemic disorders
1. Chronic disease
2. Malnutrition
3. Eating disorders
C. CNS tumors and their treatment (radiotherapy and surgery)
D. Hypothalamic-pituitary causes of pubertal failure (low gonadotropins)
1. Congenital disorders associated with GnRH or gonadotropin deficiency
(Table 403-2)
2. Acquired disorders
a. Pituitary tumors
b. Hyperprolactinemia
c. Infiltrative disorders, such as hemochromatosis
E. Gonadal causes of pubertal failure (elevated gonadotropins)
1. Klinefelter syndrome
2. Bilateral undescended testes
3. Orchitis
4. Chemotherapy or radiotherapy
5. Anorchia
F. Androgen insensitivity

TABLE 403-2 Causes of Congenital Hypogonadotropic Hypogonadism¶

Harrison's 22e, p.3112

GENE	LOCUS	INHERITANCE	ASSOCIATED FEATURES
TUBB3	Tubulin β 3	AR	Anosmia
	12q21.33	AR
GLCE	15q23	AR	Anosmia (some patients may be normosmic)
	20p12.1	AR
SPRY4	5q31.3	AR	Anosmia (some patients may be normosmic)
	3p14.3	AR
SEMA3A	7q21.11		Anosmia
	15q24.1
SEMA3E	7q21.11		Anosmia
	3q21.3
DCC	18q21.2	AR	Anosmia
	17p13.1	AR
KLB	4p14	AR	Metabolic disorders
A2. GnRH Deficiency with Normal Sense of Smell
	4q21	AR
GnRH1	8p21	AR	None
	1q32.1	AR
KISS1R	19p13	AR	None
	12q13	AR
TAC3R	4q25	AR	Microphallus, cryptorchidism, reversal of GnRH deficiency
	1p31	AR
LEP	7q31	AR	Obesity
	15q21.2	AR
OTUD4	4q31.21	AR	Ataxia (Gordon Holmes syndrome)
	7p22.1	AR
STUB1	16p13.3	AR	Ataxia
	12q23.3	AR
PNPLA6	19p13.2	AR	Ataxia (Laurence-Moon syndrome)
	Xp21.2	X-linked
CCDC141	2q31.2	AR	Normosmia
	3q25.1	AR
RNF216	7p22.1	AR	Atxia, dementia, and hypogonadotropic hypogonadism (Gordon Holmes syndrome)
B. Hypogonadotropic Hypogonadism Not Due to GnRH Deficiency
	5q15-21	AR
HESX1	3p21	AR	Septo-optic dysplasia, CPHD
	9q34	AR
PROP1	5q35	AR	CPHD (ACTH usually spared)
	11p13	AR
LHb	19q13	AR	↑ FSH
	9p33	AD/AR

TABLE 403-3 Clinical Pharmacology of Some Testosterone Formulations FORMULATION T enanthate or cypionate¶

Harrison's 22e, p.3120

FORMULATION	REGIMEN	PHARMACOKINETIC PROFILE	DHT AND E2	ADVANTAGES	DISADVANTAGES
T enanthate or cypionate	140–200 mg IM q2wk or 70–100 mg/wk	After a single IM injection, serum T levels rise into the supraphysiologic range, then decline gradually into the low-normal or the hypogonadal range by the end of the dosing interval	DHT and E2 levels rise in proportion to the increase in T levels; T:DHT and T:E2 ratios do not change	Corrects symptoms of testosterone deficiency; relatively inexpensive if self-administered; flexibility of dosing	Requires IM injection; peaks and valleys in serum T levels that are associated with fluctuations in patient’s mood, energy level, and sex drive
	Available in sachets, tubes, and pumps	When used in appropriate doses, these topical formulations restore serum T and E2 levels to the physiologic male range	Serum DHT levels and DHT:T ratio are higher in hypogonadal men treated with the transdermal gels than in healthy eugonadal men	Corrects symptoms of testosterone deficiency, ease of application, good skin tolerability
T pellets	Several pellets implanted SC; dose and regimen vary with formulation	Serum T peaks at 1 month and then is sustained in normal range for 3–4 months, depending on formulation	T:DHT and T:E2 ratios do not change	Corrects symptoms of testosterone deficiency	Requires surgical incision for insertions; pellets may extrude spontaneously
	Two different formulations of oral testosterone are available each taken orally bid with food	TU formulated in a self-emulsifying drug delivery system that includes hydrophilic and lipophilic excipients to enable the solubilization of TU and its absorption through the lymphatics after oral ingestion with a typical meal. After each administration, serum T levels rise and return to baseline by 12 h. When administered at the recommended dose, average serum T levels are maintained in the normal range in a majority of treated men	High DHT:T ratio	Convenience of oral administration
Injectable long- acting TU in oil	U.S. regimen 750 mg IM, followed by 750 mg at 4 weeks, and 750 mg every 10 weeks	When administered at the recommended dose, serum T levels are maintained in the normal range in a majority of treated men	DHT and E2 levels rise in proportion to the increase in T levels; T:DHT and T:E2 ratios do not change	Corrects symptoms of testosterone deficiency; requires infrequent administration	Requires IM injection of a large volume; serious pulmonary oil microembolism (POME) reactions, characterized by cough, dyspnea, throat tightening, chest pain, dizziness, and syncope, and episodes of anaphylaxis have been reported to occur during or immediately after the injection in a very small number of patients; patients should be watched for POME reaction for 30 min after each injection
	2 actuations of the metered-dose pump (11 mg) applied into the nostrils 3 times daily	Restores T into the normal male range	T:DHT and T:E2 ratio in the physiologic range

TABLE 403-4 Conditions in Which Testosterone Administration Should not be Used or Used with Increased Caution…¶

Harrison's 22e, p.3121

Conditions in which testosterone administration is associated with very high
risk of serious adverse outcomes:
Metastatic prostate cancer
Some types of breast cancers
Thrombophilia
Conditions in which testosterone administration is associated with moderate to
high risk of adverse outcomes and should be used with increased caution and
only after further evaluation
Undiagnosed prostate nodule or induration
PSA >3
Erythrocytosis (hematocrit >50%)
Severe lower urinary tract symptoms associated with benign prostatic
hypertrophy as indicated by American Urological Association/International
prostate symptom score >19
Uncontrolled or poorly controlled congestive heart failure
Myocardial infarction, stroke, or acute coronary syndrome in the preceding
4 months

TABLE 403-5 Monitoring Men Receiving Testosterone Therapy 1. Evaluate the patient 3–6 months after treatment initiation…¶

Harrison's 22e, p.3122

1. Evaluate the patient 3–6 months after treatment initiation and then annually
  to assess whether symptoms have responded to treatment and whether the
  patient is suffering from any adverse effects.
  2. Monitor testosterone level 3–6 months after initiation of testosterone therapy:
  • Therapy should aim to raise average serum testosterone level into the mid-
  normal range (~400–750 ng/dL).
  • Injectable testosterone enanthate or cypionate: Measure serum
  testosterone level midway between injections. If testosterone is >750 ng/dL
  (26.2 nmol/L) or <400 ng/dL (14.0 nmol/L), adjust dose or frequency.
  • Transdermal gels and solution: Assess testosterone level 2–12 h after
  patient has been on treatment for at least 2 weeks; adjust dose to
  achieve serum testosterone level in the mid-normal range (400–750 ng/dL).
  • Testosterone pellets: Measure testosterone levels at the end of the
  dosing interval. Adjust the number of pellets and/or the dosing interval
  to achieve serum testosterone levels in the normal range.
  • Oral testosterone undecanoate: Measure testosterone levels 6–8 h after
  an oral dose.
  • Injectable testosterone undecanoate: Measure serum testosterone
  level just prior to each subsequent injection and adjust the dosing
  interval to maintain serum testosterone in mid-normal range.
  3. Check hematocrit at baseline, at 3–6 months, and then annually. If hematocrit
  is >54%, stop therapy until hematocrit decreases to a safe level; evaluate the
  patient for hypoxia and sleep apnea; reinitiate therapy with a reduced dose.
  4. Measure bone mineral density of lumbar spine and/or femoral neck after
  1–2 years of testosterone therapy in hypogonadal men with osteoporosis or
  low trauma fracture, consistent with regional standard of care.
  5. In men aged ≥55 years, perform digital rectal examination and check PSA
  level before initiating treatment, at 3–6 months, and then in accordance with
  guidelines for prostate cancer screening depending on the age and race of
  the patient.
  6. Obtain urologic consultation if there is:
  • An increase in serum PSA concentration >1.4 ng/mL within the first
  12 months after starting testosterone treatment, confirmed by repeating
  the test.
  • A PSA level >4 ng/mL any time during treatment, confirmed by repeating
  the test.
  • Detection of a prostatic abnormality on digital rectal examination.
  • Severe lower urinary tract symptoms
  7. Evaluate formulation-specific adverse effects at each visit:
  • Injectable testosterone esters (enanthate, cypionate, and undecanoate):
  Ask about fluctuations in mood or libido, and rarely cough after injections.
  • Testosterone gels: Advise patients to cover the application sites with a
  shirt and to wash the skin with soap and water before having skin-to-skin
  contact because testosterone gels leave a testosterone residue on the
  skin that can be transferred to a woman or child who might come in close
  contact. Serum testosterone levels are maintained when the application
  site is washed 4–6 h after application of the testosterone gel.
  • Testosterone undecanoate injection: Observe patients for POME reaction
  for 30 min after each injection.
  • Testosterone pellets: Look for signs of infection, fibrosis, or pellet
  extrusion.
  • Intranasal testosterone: Look for signs of nasal irritation or scab.