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Evidence-Based Reviews


Teen girl brain: High drama, high risk for depression

How surging hormones make the developing brain more vulnerable to stress.

Vol. 6, No. 5 / May 2007

Kate, age 14, is referred for follow-up treatment of depression after she impulsively swallowed a bottle of acetaminophen. She says she is in academic trouble and has no friends. Kate describes her childhood as mostly happy except for her parents’ arguments. Her medical history indicates she began developing breasts at age 10 and had her first menstrual period at age 12.

Her father is largely absent, traveling and working long hours. Her mother developed postpartum depression and stopped working after Kate’s younger brother was born.

Girls and boys show similar depression risks during childhood, but girls are twice as likely as boys to become clinically depressed after puberty. The key to treating depression in teen girls is to recognize that brain development and fluctuating hormones can influence behavior in ways that confuse them and the people around them. Successfully treating teen girls’ depression may require a gender-specific approach.

3 stages of brain development

Fetal differentiation. All brains start out with female-type brain circuits. At 8 weeks of fetal life, however, tiny testicles in the male begin to produce large amounts of testosterone, which changes the brain and body to male. Thus, sex-specific genes and hormones guide aspects of the first phase of brain development.1

Table 1

Female hormonal development: Gestation to puberty

Stage/age

Hormonal events

Effect on female brain

Gestation

Components of reproductive axis form in early embryonic development; at 8 weeks, testosterone from fetal testicles begins to change female-type brain areas to male

Unperturbed by testosterone, brain continues to develop along female lines

Birth to age 24 months

Hormone-secreting placenta detaches at birth, dramatically increasing GnRH and LH/FSH and driving infant gonads to produce estrogen in girls or testosterone in boys (“infantile puberty”)

Abundant ovarian estrogen secretion enhances development of brain circuits, such as those associated with reproduction, maternal behavior, and social relatedness

Age 24 months to prepuberty

“Brakes” put on GnRH and LH/FSH pulsatile brain cells

“Juvenile pause” begins, with constant low estrogen secretion in girls by 24 months (in boys, “brakes” are on by 12 months)

Puberty

“Brakes” released on GnRH and LH/FSH neurons, reactivating reproductive axis

Ovary resumes estrogen production (“adolescent puberty”); increase in estrogen, progesterone, and testosterone stimulates brain circuit development; unipolar depression rates increase to 2:1 (female to male) by age 15

GnRH: gonadotropin-releasing hormone; LH/FSH: luteinizing hormone/follicle-stimulating hormone

Source: References 4,5

Infantile puberty and the second phase of brain development begin in early childhood, as the ovaries and testicles start to produce large amounts of estrogen and testosterone soon after birth.

Puberty launches the final brain development phase. Up to 2 years before menstruation begins, pulsatile gonadotropin-releasing hormone cells in the hypothalamus wake up and start stimulating the ovaries to produce estrogen, thrusting the girl brain into puberty (Figure). The teen girl brain begins to experience not only estrogen surges from the ovary but progesterone and testosterone surges as well.

Although brain size and basic circuitry are mostly set by age 5, puberty stimulates new brain cells and increases myelin production.2 Faster myelinated connections between emotionally impulsive limbic brain areas such as the amygdala and sensible, cognitive areas such as the prefrontal cortex are not finished until the early 20s.3

Hormonal changes at puberty

The female brain is remodeled during puberty, leading to sexually dimorphic brain activation and development that further differentiates it from the male brain.4

Estrogen surges are associated with increased production of neurohormones and neurochemicals, such as:

  • oxytocin, which reinforces social bonding and intimacy
  • dopamine, which stimulates motivation and pleasure circuits in the brain.

Hormonal changes and brain development alter gene expression and affect neurodevelopment. These events may trigger a first depression in pubertal girls with a family history of mood disorder (Table 1).4,5 Although menarche has begun at an average age of 12 in the United States for decades, the most recent National Health and Examination Survey (NHANES) shows puberty onset in girls is occurring earlier (Table 2).6-9

Tanner stage—a measure of pubertal status—is a more accurate predictor of depression in teen girls than age.10 Pubertal transition to Tanner stage 3 (development of pubic and axillary hair and breast buds) is associated with a sharp increase in depression rates. Girls at stage 3 and higher are approximately 3 times more likely to be depressed than girls at stages 1 or 2.11

Pubic hair, breast development, and menstruation are markers for underlying hormonal changes (Table 3).4,5 The onset of estrogen, progesterone, and testosterone surges closely correlates with the difference in depression rates between pre- and postpubertal girls.12 After estrogen and progesterone surges begin at puberty, negative emotions exert an increased activating effect on the female brain,13 and social stressors more deeply affect girls than they do boys. This may explain why girls are more susceptible to depression when a friendship fails.14

CASE CONTINUED: Boy troubles

Kate tells you that in 9th grade she and her best friend, Ellen, would talk about boys for hours after school and try on sexually provocative outfits. They both liked Matt, a 10th grader, so when he asked Kate out, Ellen stopped speaking to her. Kate and Matt began some heavy petting, and Kate said she felt selfish and guilty about hurting Ellen. But when girls at school began spreading rumors that Kate was a “slut,” Kate blamed Ellen and told her, “I hate you!”

Soon after, Matt broke up with Kate. Distraught, she dreaded going to school and cried in her room at night for several weeks. She became chronically tired and had difficulty concentrating in class. She ruminated about losing Matt and worried that she was too fat, too ugly, or too flat-chested. She missed Ellen and felt no one liked her.

Table 2

Puberty’s developmental milestones in U.S. girls (averages)

Correlate

African Americans

Whites

School grade*

Breast bud development

Age 9

Age 10

4th to 5th

Girls with puberty onset by age 8

32%

11%

3rd

Girls with puberty onset by age 10

76%

53%

5th

Menarche onset

Age 12.1

Age 12.6

7th

Tanner stage 5 onset

Age 13.9

Age 15.5

8th to 9th

* Approximate grade level for age groups

† Pubic hair and breast development reach adult stage

Source: Data from references 6-9, including the Pediatric Research in Office Settings network and Third National Health and Nutrition Examination Survey, 1988-1994.

Figure Hypothalamic-pituitary-ovarian axis: Turned on at puberty in girls



Puberty onset stimulates depression in genetically vulnerable girls; more likely after Tanner stage 3 (development of pubic and axillary hair and breast buds).

Male vs female teen brains

Depression after a relationship failure in teen girls often begins with ruminative thoughts about her flaws, mistakes, or appearance. These negative thoughts may preoccupy her day and night. Teen girls often feel confused by contradictory social pressures to look and dress provocatively but resist having sex. A sexual encounter can trigger shame and fear.

Although clinical and developmental studies indicate that teen girls respond more dramatically to relationship troubles than boys, the brain and hormone differences responsible for these effects remain unclear. Male hormones hugely increase in boys at puberty—up to 25-fold between ages 9 and 15—but do not cycle. Male brains do not have the same capacity as female brains to respond to cyclical hormonal activity because exposure to androgens during fetal development eliminates this ability. The fetal testosterone surge causes the area associated with sexual pursuit to double in the male brain.

Outside of fertility considerations, Baron-Cohen et al15 suggest that male brain circuits have been formed by fetal testosterone to focus more on systematization—which emphasizes figuring out how things work and performing tasks—rather than empathy and bonding in relationships. This difference has been shown in neuroimaging studies comparing the genders’ attentional systems.16,17 In contrast to the systematizing male brain, female brains are more likely to activate the mirror neuron system—the area required for empathizing.18

Female brains, of course, respond to cyclical hormonal activity. However, the regular monthly waves of estrogen and progesterone do not affect all female brains the same. A subset of women who experience premenstrual dysphoric disorder appear to have brains that trigger depressed moods and irritability during the last 2 weeks of the menstrual cycle.19 A genetic difference in these women is suspected as the culprit; these genes may affect the way their brains metabolize progesterone.

CASE CONTINUED: An overdose of stress

Kate’s poor concentration lingered, and her grades continued to drop. She tells you her parents were having marital problems and she did not want to bother them with her difficulties. Two days before her period was due, she learned she had failed 2 classes. That night, as she got some acetaminophen for a headache, she impulsively took the rest of the bottle.

After swallowing the pills, Kate panicked. She forced herself to vomit and tearfully told her parents what she had done. They took her to the emergency room, where she was medically stabilized, evaluated by a psychiatrist, and referred to you for outpatient treatment.

Treatment recommendations

A combination of factors—genetic, hormonal, and neurodevelopmental—probably contributed to Kate’s acute depressed mood and overdose. Thus, to treat depression in adolescent girls, emerging evidence supports:

  • stabilizing hormonal fluctuations such as rapidly falling progesterone just before the start of menstrual periods with an extended-cycle contraceptive (we would try an ethinyl estradiol/levonorgestrel combination such as Seasonale®)
  • treating depressive symptoms with a selective serotonin reuptake inhibitor such as citalopram, 10 mg once daily, with careful monitoring for suicidal thoughts or behavior
  • providing tools to manage stress and impulsive behavior through weekly psychotherapy (such as cognitive-behavioral therapy, dialectical behavioral therapy, or supportive therapy).

Genetic factors. Kate’s mother’s history of postpartum depression suggests genetic risk for Kate. Studies have found that the expression of particular genes—such as the serotonin transporter (5-HTT) gene—may be associated with depression. Staley et al20 found that depressed women show a significantly greater decrease in 5-HTT availability in the diencephalon (forebrain region containing the thalamus, hypothalamus, and part of the pituitary gland) when compared with healthy women and depressed men.

Table 3

3 stages of girls’ gonadal development

Stage

Timing

Developmental events

Adrenarche

Onset around age 6, peaks by age 20

Rise in weak androgens (DHEA and DHEAS) from adrenal gland results in pubic and axillary hair and increases likelihood of acne

Gonadarche

Usually ~2 years before menarche

Pulses of GnRH, LH/FSH lead to increased estrogen, which stimulates breast development, widening of hips, and increased subcutaneous fat deposition

Menarche

Relatively late in puberty (usually not before Tanner stage 4)

“Monthly” cycle established; ovarian estrogen pulses in response to GnRH and FSH, the LH surge, and ovulation; progesterone produced after ovulation

DHEA: dehydroepiandrosterone; DHEAS: dehydroepiandrosterone sulfate; GnRH: gonadotropin-releasing hormone;

LH/FSH: luteinizing hormone/follicle-stimulating hormone

Tanner stage 4: pubic hair and breast development typical of middle to late adolescence (ages 12 to 17)

Source: References 4,5

Although men and women have the same 5-HTT gene, women may possess a gender-specific factor—such as estrogen or progesterone—that differentially alters this and other genes’ expression in women with depression. Individuals who carry a short version of the gene may be at particular risk of becoming depressed when exposed to stressful life events.

Caspi et al21 found a polymorphism in the 5-HTT gene on chromosome 17 that can manifest differentially based on environmental factors. In this study, individuals with 2 copies of the long version of this gene were relatively resistant to stressful life events, whereas those with 1 or 2 copies of the short version were highly sensitive to stressful life events. The depression rate in short-gene individuals was:

Continued...
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