Growth and Puberty Flashcards
Growth plate
- aka physis
- Area lying at the end of growing bones that expands during growth
- Consists of layers of chondrocytes
- Proliferating in distal area, progeny move proximally and hypertrophy, then lay down collagen
- When proximally-moving chondrocytes hit the formed bone, they undergo apoptosis and trigger local angiogenesis
- This allows the matrix they created to be ossified by invading osteoblasts, then remodeled by osteoclasts.
IGF-1
- Produced by liver in response to GH
- Negatively feedback inhibits GH
- Carried through plasma by IGF-BP3 and acid labile subunit (which are also produced in the liver in response to GH)
- Binds to IGF-1R on cells at the growth plate to stimulate growth.
Fetal growth
- Dependent upon IGF-1, but NOT upon GH
- Insulin is also an important fetal growth factor
Growth velocity
Measured in cm/year
Declines throughout childhood, but then peaks again with a nadir during puberty.
Individuals with a LoF mutation in aromatase or the estrogen receptor are often ___.
Individuals with a LoF mutation in aromatase or the estrogen receptor are often tall
This is because they are usually not diagnosed until late puberty-age, and have had uninhibited growth plates which have continued to elongate in the absence of estrogen. Once estrogen is administered, their growth plates will calcify and their growth will stop.
Causes of growth plate-intrinsic growth retardation
- Chromosomal anomalies, especially Down’s syndrome and Turner’s syndrome
- Infants born small for gestational age (SGA) - may be due to maternal factors such as placental insufficiency, pre-eclampsia, or drug use, or due to infant factors such as congenital infection or numerous genetic etiologies
- Congenital cartilage or bone disorders, aka osteochondrodysplasias
- Most common is achondroplasia, an autosomal dominant mutation in FGFR3 that results in severe proximal limb shortening and large head size.
Causes of regulatory-malfunction induced growth retardation
- Malnutrition, including due to anorexia nervosa
- Chronic illness of almost any organ system
- Disorders of hormones that regulate growth - Cushing’s syndrome. hypothyroidism, primary or secondary IGF-1 deficiency
Secondary IGF-1 deficiency
- Caused by GH deficiency
- Acquired causes may be anything damaging the anterior pituitary
- Congenital causes include brain malformations and rare genetic mutations in GH or the GHRH receptor
Primary IGF-1 deficiency
- Very rare
- Characterized by very low IGF-1 levels but elevated GH levels
- May be due to defects in IGF-1 itself, defects in GH bioactivity, in the GH receptor, or in the acid labile subunit of IGF-1’s soluble transporter
McCune-Albright Syndrome
Constitutive activation of the GHRH receptor by somatic mutations in the stimulatory G-protein α-subunit GNAS
Results in dysregulated GH production, excessive growth, areas of bone dysplasia, and cafe-au-lait spots.
Treating GH deficiency
- Recombinant human GH (aka somatotrophin)
- Administered via daily injection
- Rare side effects include idiopathic intracranial hypertension, slipped capital femoral epiphysis, and hyperglycemia
Treating primary IGF-1 deficiency
- Recombinant IGF-1 (mecasermin)
- Main side effect is hypoglycemia due to cross-reactivity with the insulin receptor
Composition of an ovarian follicle
- Primary oocyte (germ cell arrested in first meiotic division)
- Supporting granulosa cells
- Surrounding the follicle, but not part of it, are theca cells, which produce androstenedione
Ovary histology
Uterus and ovary anatomy in coronal section
Uterine histology
Saggital section of breast tissue
Testes histologic section
Diagram of seminiferous tubule arrangement
Spermatogonia cells
Spermatogonia proliferate via asymmetric mitosis to regenerate themselves and to form a primary spermatocyte, making spermatogonia a type of stem cell.
Primary spermatocytes then enter meiosis, going through both rounds (instead of just one as ova do) during gametogenesis. This generates four spermatids. These spermatids must them mature into sperm cells.
Mature sperm migration
Once matured, sperm cells migrate to the lumen of the seminiferous tubules, then out of the tubules to the epididymis, where they are stored.
During ejaculation, the sperm cells travel down the vas deferens. At the distal vas deferens, fluid contributions from the seminal vesicles and the prostate gland are added. Then, the sperm continue down into the urethra.
Cross-sectional anatomy of the penis
How the penis becomes rigid
- Parasympathetic tone increases, causing vasodilation of the deep artery of the penis that fills the corpora cavernosa with fluid.
- The expansion of the corpora cavernosa flattens their own draining vein, the deep dorsal vein, between the cavernosa and the tunica albuginea, decreasing venous outflow
- The combination of increased inflow and decreased outflow leads to fluid accumulation, causing erection
- Once ejaculation occurs, the artery constricts again, and gradually the corpora cavernosa will empty and decompress the vein, returning the penis to its original state.
Pattern of GnRH release and LH/FSH
The pulsatile nature of GnRH secretion is critical to its stimulation of LH and FSH release.
In fact, continuous (nonpulsatile) exposure to GnRH actually suppresses LH and FSH secretion, and this effect underlies the utility of potent GnRH analogues for suppressing the HPG axis to treat precocious puberty.
GnRH regulation
GnRH secretion is suppressed by starvation, stress, systemic illness, estradiol, progesterone.
In contrast, GnRH secretion is potently and selectively stimulated by a hormone called kisspeptin, which is produced by a distinct population of hypothalamic neurons
GnRH neuron embryology
Embryologically, GnRH neurons originate in the nasal placode and migrate into the central nervous system, which explains why some congenital defects of GnRH neurons are associated with anosmia
LH in testes
LH acts on the LH/hCG receptor on Leydig cells to stimulate the production of testosterone.
Circulating testosterone exerts negative feedback indirectly by being converted to estradiol locally in the hypothalamus via aromatase. This estradiol then inhibits GnRH, LH, and FSH.
Inhibins produced in the testes also suppress FSH seletively.
LH/FSH in ovaries
In ovaries, estrogen production requires both LH and FSH.
LH stimulates theca cells to produce androstenedione. Some androstenedione is then converted to estradiol in granulosa cells via the action of FSH. This estadiol then feedback inhibits GnRH/LH/FSH.
Progesterone produced here also suppresses GnRH, and inhibins produced here selectively suppress FSH.
Mixed gonadal dysenesis
Due to loss of the Y chromosome unilaterally.
Testis develops on one side and ovary on the other, usually neither complete.
Hormones critical for male sex organ development
- Anti-müllerian hormone (AMH) from Sertoli cells
- Testosterone from Leydig cells
- Dihydrotestosterone for external genitalia
- The undifferentiated fetus has two sets of primordial internal genitalia, the müllerian ducts and the wolffian ducts. In the presence of testes, AMH causes regression of the fetal müllerian ducts, which otherwise develop into the uterus, fallopian tubes, and upper third of the vagina. In addition, testosterone stabilizes the fetal wolffian ducts and promotes their development into the vas deferens, seminal vesicles, and epididymis. In the absence of testosterone, the wolffian ducts degenerate
Development of male and female genital tracts
Dihydrotestosterone in external male genitalia development
- 5α-reductase type 2 in genital skin converts testosterone to dihydrotestosterone
- DHT is the primary hormone responsible for masculinizing the external genitalia, including enlarging the genital tubercle to form a penis and fusing the labioscrotal folds into a scrotum
- In the absence of DHT, these undifferentiated structures develop into the clitoris and labia majora, respectively.
- Testicular descent into the scrotum also requires testosterone and generally occurs in the final 6 weeks of gestation.
Androgens in first trimester sex organ development
- The first trimester is the only period during which the labioscrotal folds are susceptible to fusion.
- If a female fetus is exposed to excess androgens during the first trimester, the clitoris and labioscrotal folds will virilize and will form a typical male penis and scrotum, although no testes will be present in the scrotum.
- Conversely, inadequate testosterone or DHT synthesis or action in a male fetus at this stage will cause undervirilization.
When does the fetal pituitary develop?
During the second trimester.
Thus, all sex organ development during the first trimester is due to action of placental hCG, which acts at LH receptors and can stimulate other hormones. In Leydig cells, it stimulates testosterone production.
Second and third trimester sex organ development
- Begins after fetal pituitary matures
- In males: Pituitary-derived LH is responsible for changes in penile morphology, scrotal maturation, and testes descent
- In females: Excess hormone no longer causes scrotum formation, but may lead to clitoris enlargement. Labia enlarges.
Androgen insensitivity syndrome
- Androgen receptor is encoded by the AR gene on the X-chromosome, so X*Y individuals cannot respond to testosterones
- Testes develop and produce testosterone and AMH normally due to SRY
- AMH appropriately causes müllerian regression
- Lack of testosterone fails to support wolffian ducts
- The result is development of female external genitalia, and so this often missed at birth unless genetic testing is done
- At puberty, testes produce testosterone, but individual does not develop male sex characteristics. Instead, aromatization converts to estrogen and female sex characteristics develop.
- Often present because they do not undergo menarche, and under scrutiny condition is uncovered.
- Usually identify with the female gender
“Puberty” vs “Adolescence”
Puberty describes the physical changes that occur during adolescence.
Adolescence is the developmental period during which puberty occurs, as well as a complex series of cognitive, social, and emotional changes that mark the transition from childhood to adulthood
Beginning in infancy and throughout childhood, the HPG axis is ___.
Beginning in infancy and throughout childhood, the HPG axis is quiescent
It only reactivates again during puberty. Pulsatile GnRH secretion begins slowly, at first occurring at low levels and only at night, but over time GnRH pulses become larger and more frequent and occur throughout the day
Thelarche
The onset of breast development in pubescent females
Driven by estradiol, which stimulates development of the mammary glands and increased fat deposition in the breast.
Pubarche
The development of pubic hair
Result of circulating androgens
Effects of circulating androgens in puberty
- pubarche
- axillary and facial hair growth
- body odor development
- acne
Growth acceleration during puberty
Driven by the stimulatory effects of sex steroids on GH secretion, as well as their direct growth-stimulating effects on the growth plate.
Adrenarche
- Activation of the zona reticularis
- Partly responsible for the development of pubic and axillary hair, body odor, and acne
- Effects are more notable in those with typical female phenotypes, as their effects are overshadowed by testosterone in males
Adrenarche and gonadarche are ___
Adrenarche and gonadarche are independent events
Patients with isolated adrenal insufficiency have normal gonadarche, and patients with isolated defects of the HPG axis have normal adrenarche
Tanner stages for females
Tanner stages for males
M and F puberty timelines
Delayed puberty
- Absence of thelarche by age 12-13 in girls or absence of testicular enlargement in boys by age 13.5-14 (both +2 z-score)
- Adrenarche may be present
- Impaired function at some level of the HPG axis
- Serum levels of LH, FSH, and estradiol (in girls) or testosterone (in boys) are appropriate to confirm and localize the defect
- Bone age test
Bone age
- Degree of skeletal maturation
- Assessed by comparing an x-ray of the patient’s hand to sex-specific standard x-ray images
- A bone age that is younger than the patient’s chronologic age suggests less sex steroid exposure than is typical and may support a diagnosis of pubertal delay.
Primary hypogonadism
- Elevated LH/FSH, but low testosterone or estradiol
- Impaired function of BOTH gonads
- Most common cause is Turner syndrome (45,X) in females, which causes ovarian dysgenesis in utero
- Acquired causes include damage to the gonads from trauma (including bilateral testicular or ovarian torsion), chemotherapy, radiation, or autoimmune inflammation.
Secondary hypogonadism
- Caused by impaired pituitary secretion of LH and FSH
- Congenital causes include hypothalamic-pituitary malformations or mutations in a number of genes involved in GnRH neuron development
- Defects in olfactory bulb formation cause anosmia and secondary hypogonadism. (Kallmann syndrome)
- Acquired may be due to trauma, radiation, tumors/infiltrative disease, or by hyperprolactinemia or hypothyroidism
- GnRH secretion is also suppressed by starvation, stress, and systemic illness, and any of these states can also cause delayed puberty
Constitutional delay
- A common cause of delayed puberty (particularly in boys) that is not pathological but rather a variant of normal
- Delayed, but individuals will eventually spontaneously undergo puberty on their own w/o intervention
- Runs in families, but mechanism is unknown
- Biochemically, constitutional delay cannot be distinguished from other forms of secondary hypogonadism, so it must be diagnosed presumptively based on family history, delayed bone age, and exclusion of other causes
- Only definitive when the patient enters puberty
Treatment of delayed puberty
- Replacing the absent gonadal hormone (testosterone or estradiol) to induce the normal physical changes of puberty
- In individuals with a uterus, cyclic progesterone is added to estradiol once breast and uterine development have occurred to induce menses and ensure endometrial health
Precocious puberty
- Defined statistically as the onset of thelarche before age 7-8 in girls or of testicular enlargement before age 9 in boys
- Early or excessive HPG axis activity, or autonomous gonadal activity
- Major complications of precocious puberty are psychosocial problems from the development of secondary sex characteristics at an inappropriately young age
- Short stature resulting from premature growth plate closure is another component
Central precocious puberty
- Abnormally elevated levels of LH, FSH, and estradiol or testosterone in a child prior to the normal age of puberty
- Often idiopathic
- May be caused by structural lesions such as congenital malformations, hydrocephalus, trauma, irradiation, tumors, or benign masses, particularly hamartomas of the hypothalamus
Peripheral precocious puberty
- Characterized by elevated estradiol or testosterone with appropriate suppression of LH and FSH.
- Excess estradiol or testosterone may come from exogenous administration, from a tumor, or from primary gonadal overproduction
Premature adrenarche
- Premature zona reticularis activation prior to age 7-8 in girls or age 9 in boys
- can lead to early appearance of pubic or axillary hair, body odor, or acne
- Symptoms are often mistaken for evidence of central precocious puberty, which can be ruled out if breast development or testicular enlargement is not present
Treating precocious puberty
-
Central precocious puberty is treated by suppressing abnormal LH and FSH secretion using a long-acting analog of GnRH (such as leuprolide), typically given by depot injection.
- Remember that continuous GnRH inhibits LH/FSH!
- This suppression is reversible when the GnRH analog is withdrawn, at an age appropriate for pubertal development
-
Peripheral precocious puberty treatment depends on the cause
- Exogenous sex steroids can be withdrawn and hormonally active tumors resected
- Intrinsic hyperfunction of the gonads is treated with medications that block sex hormone production or action
“Normal” range of beginning puberty for males/females
- Females: Puberty ~10, menarche ~12
- Males: Puberty ~11
Approach to amenorrhea
Workup for hypergonadotropic hypogonadism
- Karyotype first (Turner’s syndrome/45,X is most common)
- Genetic tests
- Anatomical assessment
- Pathology to assess for ovarian fibrosis/autoimmunity
The first hormone that the ovaries make is ____.
The first hormone that the ovaries make is testosterone.
This must then be converted to estradiol.
Midparental height
- Average parental height (+ 2.5 for boys, - 2.5 for girls)
- Can be a useful reference value for differentiating familial short stature vs a genetic or acquired hormonal deficiency or other pathology.
