3025 Disorders of the Testes and Male Reproductive System CHAPTER 391

rate of progression of coronary artery atherosclerosis did not differ

between the testosterone- and placebo-treated men. In another

randomized trial, compared to placebo, testosterone treatment was

associated with greater increase in noncalcified plaque volume in

the coronary arteries, assessed using CT coronary angiography. An

ongoing large prospective randomized trial (TRAVERSE trial) will

determine the effects of testosterone replacement therapy on major

adverse cardiovascular events in middle-aged and older hypogonadal men at increased risk of CVD.

Androgen Abuse by Athletes and Recreational Bodybuilders The

illicit use of androgenic-anabolic steroids (AAS) to enhance athletic

performance first surfaced in the 1950s among powerlifters and

spread rapidly to other sports, professional as well as high school

athletes, and recreational bodybuilders. In the early 1980s, the use

of AAS spread beyond the athletic community into the general

population, and now, as many as 3–4 million Americans—most of

them men—have likely used these compounds. Most AAS users are

not athletes, but rather recreational weightlifters, almost all men,

who use these drugs to look lean and more muscular. A subset of

AAS users suffers from muscle dysmorphia, a form of body image

disorder characterized by excessive preoccupation with leanness

and muscularity and poor functioning in social and occupational

life. A secular transformation in idealized body image toward

greater muscularity and leanness has contributed to increasing

prevalence of body image disorders and the use of muscle-building

anabolic drugs in young men.

The most commonly used AAS include testosterone esters, nandrolone, stanozolol, methandienone, and methenolol. AAS users

generally use large doses of multiple steroids in cycles, a practice

known as stacking. AAS users may also typically use other drugs

that are perceived to be muscle building or performance enhancing, such as human GH; erythropoiesis-stimulating agents; insulin;

stimulants such as amphetamine, clenbuterol, cocaine, ephedrine,

and thyroxine; and drugs perceived to reduce adverse effects such

as hCG, aromatase inhibitors, or estrogen antagonists. Recent years

have witnessed increasing use of unapproved nonsteroidal SARMs

and GH secretagogues purchased from internet sites.

Most of the information about the adverse effects of AAS has

emerged from case reports, uncontrolled studies, or clinical trials

that used replacement doses of testosterone. The adverse event

data from clinical trials using physiologic replacement doses of

testosterone have been extrapolated unjustifiably to AAS users, who

may administer 10–100 times the replacement doses of testosterone

over many years, to support the claim that AAS use is safe and

manageable. The adverse events associated with AAS use may be

due to AAS themselves, concomitant use of other drugs, high-risk

behaviors, and host characteristics that may render these individuals more susceptible to AAS use or to other high-risk behaviors.

The high rates of premature mortality and morbidities observed

in AAS users are alarming. One Finnish study reported 4.6 times the

risk of death among elite powerlifters compared with age-matched

men from the general population. The causes of death among powerlifters included suicides, myocardial infarction, and liver failure.

A retrospective review of patient records in Sweden also reported

higher standardized mortality ratios for AAS users than for nonusers

and increased death rates due to suicide, homicide, and accidents.

Four categories of adverse events associated with AAS abuse

are of particular concern: cardiovascular events, psychiatric, prolonged suppression of the hypothalamic-pituitary-testicular axis,

and potential neurotoxicity. Numerous reports of premature cardiac

death among young AAS users raise concerns about the adverse

cardiovascular effects of AAS. High doses of AAS may induce

proatherogenic dyslipidemia, accelerate atherogenesis, increase

thrombosis risk via effects on clotting factors and platelets, and

induce vasospasm through their effects on vascular nitric oxide.

Long-term AAS use may be associated with myocardial hypertrophy and fibrosis. Myocardial tissue of powerlifters using AAS has

been shown to be infiltrated with fibrous tissue and fat droplets.

Current AAS users display significantly reduced left ventricular systolic and diastolic function compared to previous users

and nonusers. Additionally, studies using CT angiography have

reported higher coronary artery plaque volume in AAS users than

TABLE 391-5 Monitoring Men Receiving Testosterone Therapy

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 serum testosterone level into the mid-normal

range.

• Injectable testosterone enanthate or cypionate: Measure serum

testosterone level midway between injections. If testosterone is >600 ng/

dL (20.9 nmol/L) or <350 ng/dL (12.2 nmol/L), adjust dose or frequency.

• Transdermal patches: Assess testosterone level 3–12 h after application

of the patch; adjust dose to achieve testosterone level in the mid-normal

range.

• Buccal testosterone bioadhesive tablet: Assess level immediately before

application of fresh system.

• 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.

• 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 4–6 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 ≥40 years with baseline PSA >0.6 ng/mL, 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 any 12-month

period of 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.

• An AUA/IPSS prostate symptom score of >19 along with an increase in IPSS

score of ≥5 points above baseline.

7. Evaluate formulation-specific adverse effects at each visit:

• Buccal testosterone tabletsa

: Inquire about alterations in taste and examine

the gums and oral mucosa for irritation.

• Injectable testosterone esters (enanthate, cypionate, and undecanoate): Ask

about fluctuations in mood or libido, and rarely cough after injections.

• Testosterone patches: Look for skin reaction at the application site.

• 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.

a

Not approved for clinical use in the United States.

Abbreviations: AUA/IPSS, American Urological Association International Prostate

Symptom Score; POME, pulmonary oil microembolism; PSA, prostate-specific antigen.

Source: Modified with permission from S Bhasin et al: Testosterone therapy in

men with androgen deficiency syndromes: an Endocrine Society clinical practice

guideline. J Clin Endocrinol Metab 95:2536, 2010.

3026 PART 12 Endocrinology and Metabolism

in nonusers. Lifetime AAS dose is strongly associated with coronary

atherosclerotic burden. Power athletes using AAS often have short

QT intervals but increased QT dispersion, which may predispose

them to ventricular arrhythmias.

Unlike replacement doses of testosterone, which are associated with

only a small decrease in HDL cholesterol and little or no effect on total

cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels, supraphysiologic doses of testosterone and orally administered 17α-alkylated, nonaromatizable AAS are associated with marked

reductions in HDL cholesterol and increases in LDL cholesterol.

Some AAS users develop hypomanic and manic symptoms (irritability, aggressiveness, reckless behavior, and occasional psychotic symptoms, sometimes associated with violence) during AAS exposure, and

depression, sometimes associated with suicidality, during AAS withdrawal. Users may also be susceptible to other forms of illicit drug use.

Long-term AAS use suppresses LH, FSH, and testosterone production and spermatogenesis. Men who have used AAS for more

than a few months experience marked suppression of the hypothalamic-pituitary-testicular (HPT) axis after stopping AAS that may

be associated with sexual dysfunction, fatigue, infertility, depressed

mood, and even suicidality. In some long-term AAS users, recovery of the HPT axis may take a long time, may be incomplete, or

may never occur. The symptoms of androgen deficiency caused by

androgen withdrawal may cause some men to revert back to using

AAS, leading to continued use and AAS dependence. As many

as 30% of AAS users develop a syndrome of AAS dependence,

characterized by long-term AAS use despite adverse medical and

psychiatric effects. AAS withdrawal hypogonadism has emerged as

an important cause of androgen deficiency, accounting for a substantial fraction of testosterone prescriptions in many men’s health

clinics; therefore, AAS use should be considered in the differential

diagnosis of hypogonadism in young men.

Supraphysiologic doses of testosterone may also impair insulin

sensitivity. Orally administered androgens also have been associated with insulin resistance and diabetes.

AAS users are more likely to engage in high-risk behaviors such

as unsafe injection practices and have increased rates of incarceration that may render them at increased risk of HIV and hepatitis B

and C. AAS users are more likely to report high-risk unprotected

anal sex than nonusers.

Elevated liver enzymes, cholestatic jaundice, hepatic neoplasms,

and peliosis hepatis have been reported with oral, 17α-alkylated

AAS. AAS use may cause muscle hypertrophy without compensatory

adaptations in tendons, ligaments, and joints, thus increasing the risk

of tendon and joint injuries. Upper extremity tendon ruptures are

observed almost exclusively among weightlifters who use AAS. AAS

use is associated with acne, baldness, and increased body hair.

APPROACH TO THE PATIENT

Androgenic-Anabolic Steroids Use

The suspicion of AAS use should be raised by increased hemoglobin and hematocrit levels, suppressed LH and FSH and testosterone

levels, low HDL cholesterol, and low testicular volume and sperm

density in a person who looks highly muscular. In AAS users

seeking medical attention, evaluation using the Appearance and

Performance Enhancing Drug Use Schedule (APEDUS), a validated

semi-structured interview, is sufficient to assess the associated

body image or eating disorder, psychiatric symptoms, and the use

of AAS and other substances; formal testing for AAS usually is not

needed. History of AAS use should be obtained in all young men

being evaluated for hypogonadism. As AAS use is often associated

with the use of other substances, a urine dug screen for other

substances is helpful in guiding treatment. If needed, accredited

laboratories use gas chromatography–mass spectrometry or liquid

chromatography–mass spectrometry to detect anabolic steroid

abuse. High-resolution mass spectrometry and tandem mass

spectrometry have further improved the sensitivity of detecting

AAS use. Illicit testosterone use is detected generally by the measurement of urinary testosterone-to-epitestosterone ratio and further confirmed by the 13C:12C ratio in testosterone using isotope

ratio combustion mass spectrometry. Exogenous testosterone

administration increases urinary testosterone glucuronide excretion and consequently the testosterone-to-epitestosterone ratio.

Ratios >4 suggest exogenous testosterone use but can also reflect

genetic variation. Genetic variations in the uridine diphospho-glucuronyltransferase 2B17 (UGT2B17), the major enzyme for testosterone glucuronidation, affect the testosterone-to-epitestosterone

ratio. Synthetic testosterone has a lower 13C:12C ratio than endogenously produced testosterone, and these differences in 13C:12C ratio

can be detected by isotope ratio combustion mass spectrometry,

which is used to confirm exogenous testosterone use in individuals

with a high testosterone-to-epitestosterone ratio.

The treatment of AAS use disorder requires a multidisciplinary

team that includes an endocrinologist or an internist to treat the

AAS withdrawal hypogonadism and other medical problems; a

mental health expert to treat the substance use disorder and depressive symptoms and to address suicide risk and body image disorder;

and sometimes a social worker for care coordination. In patients

who are willing to stop or who have already stopped AAS use, the

initial step is to restore the hypothalamic-pituitary-gonadal axis by

administering either clomiphene (or its enantiomer trans enclomiphene), a partial estrogen agonist, at an initial dose of 50 mg daily

or hCG at a dose of 750–1000 IU three times weekly. Some men

may not respond to clomiphene and may require switching to hCG.

AAS users also need evaluation and treatment of the underlying

body image disorder. Mirror exposure therapy in which the patient

stands in front of a mirror and describes his body appearance to

the mental health provider has been moderately efficacious in

small, randomized trials. Body dysmorphia may require cognitivebehavioral therapy or pharmacotherapy using selective serotonin

uptake inhibitors or tricyclic antidepressants.

■ FURTHER READING

Bangalore KK et al: Use of gonadotropin-releasing hormone analogs

in children: Update by an International Consortium. Horm Res Paediatr 91:357, 2019.

Bhasin S: Testosterone replacement in aging men: An evidence-based

patient-centric perspective. J Clin Invest 131: e146607, 2021.

Bhasin S et al: Testosterone therapy in men with hypogonadism: An

Endocrine Society Clinical Practice Guideline. J Clin Endocrinol

Metab 103:1715, 2018.

Finkelstein JS et al: Gonadal steroids and body composition, strength,

and sexual function in men. N Engl J Med 369:1011, 2013.

Hildebrandt T et al: Body image disturbance in 1000 male appearance

and performance enhancing drug users. J Psychiatr Res 44:841, 2010.

Hollis B et al: Genomic analysis of male puberty timing highlights

shared genetic basis with hair color and lifespan. Nat Commun

11:1536, 2020.

Hughes JF, Page DC: The biology and evolution of mammalian Y

chromosomes. Annu Rev Genet 49:507, 2015.

Jasuja R et al: Estradiol binding induces bidirectional allosteric coupling and repartitioning of sex hormone binding globulin monomers

among various conformational states. iScience 24:102414, 2021.

O’Shaughnessy PJ et al: Alternative (backdoor) androgen production

and masculinization in the human fetus. PLoS Biol 17:e3000002, 2019.

Pope HG Jr et al: Adverse health consequences of performanceenhancing drugs: An Endocrine Society scientific statement. Endocr

Rev 35:341, 2014.

Sedlmeyer IL et al: Delayed puberty: Analysis of a large case series

from an academic center. J Clin Endocrinol Metab 87:1613, 2002.

Snyder PJ et al: Effects of testosterone treatment in older men. N Engl

J Med 74:611, 2016.

Stamou MI et al: Kallmann syndrome: Phenotype and genotype of

hypogonadotropic hypogonadism. Metabolism 86:124, 2018.

3027 Disorders of the Female Reproductive System CHAPTER 392

Travison TG et al: Harmonized reference ranges for circulating testosterone levels in men of four cohort studies in the USA and Europe.

J Clin Endocrinol Metab 102:1161, 2017.

Weems PW et al: The roles of neurokinins and endogenous opioid peptides in control of pulsatile LH secretion. Vitam Horm 107:89, 2018.

Zakharov MN et al: A multi-step, dynamic allosteric model of testosterone’s binding to sex hormone binding globulin. Mol Cell Endocrinol 399:190, 2015.

The female reproductive system regulates the hormonal changes

responsible for puberty and adult reproductive function. Normal

reproductive function in women requires the dynamic integration of

hormonal signals from the hypothalamus, pituitary, and ovary, resulting in repetitive cycles of follicle development, ovulation, and preparation of the endometrial lining of the uterus for implantation should

conception occur.

For further discussion of related topics, see the following chapters:

amenorrhea and pelvic pain (Chap. 393), infertility and contraception

(Chap. 396), menopause (Chap. 395), disorders of sex development

(Chap. 390), and disorders of the male reproductive system (Chap. 391).

DEVELOPMENT OF THE OVARY AND EARLY

FOLLICULAR GROWTH

The ovary orchestrates the development and release of a mature oocyte

and secretes hormones (e.g., estrogen, progesterone, inhibins A and B,

relaxin) that play critical roles in a variety of target tissues, including

breast, bone, and uterus, in addition to the hypothalamus and pituitary.

To achieve these functions in repeated monthly cycles, the ovary undergoes some of the most dynamic changes

of any organ in the body. Primordial

germ cells can be identified by the third

week of gestation, and their migration to

the genital ridge is complete by 6 weeks

of gestation. Germ cells persist within

the genital ridge, are then referred to as

oogonia, and are essential for induction

of ovarian development. In patients with

45,X Turner syndrome, primordial germ

cells proliferate and migrate to the genital

ridge but do not persist because their

survival requires pregranulosa cells that

are dependent on the presence of both X

chromosomes (Chap. 390).

The germ cell population expands,

and starting at ~8 weeks of gestation,

oogonia begin to enter prophase of the

first meiotic division and become primary oocytes. This allows the oocyte

to be surrounded by a single layer of

flattened granulosa cells to form a primordial follicle (Fig. 392-1). Granulosa

cells are derived from mesonephric cells

that migrate into the ovary early in its

development, pushing the germ cells

to the periphery. Although there is evidence that both oocyte-like cells and

392 Disorders of the Female

Reproductive System

Janet E. Hall, Anuja Dokras

follicle-like structures can form from embryonic stem cells in culture,

there is, as yet, no clear evidence that this occurs in vivo, and thus, the

ovary appears to contain a nonrenewable pool of germ cells. Through

the combined processes of mitosis, meiosis, and atresia, the population of oogonia reaches its maximum of 6–7 million by 20 weeks in

the fetus, after which there is a progressive loss of both oogonia and

primordial follicles through the process of atresia. It appears that entry

into meiosis provides some degree of protection from programmed

cell death. At birth, oogonia are no longer present in the ovary, and

only 1–2 million germ cells remain in the form of primordial follicles

(Fig. 392-2). The oocyte persists in prophase of the first meiotic division until just before ovulation, when meiosis resumes.

The quiescent primordial follicles are recruited to further growth and

differentiation through a highly regulated process that limits the size

of the developing cohort to ensure that folliculogenesis can continue

throughout the reproductive life span. This initial recruitment of primordial follicles to form primary follicles (Fig. 392-1) is characterized

by growth of the oocyte and the transition from squamous to cuboidal

granulosa cells. The theca interna cells that surround the developing

follicle begin to form as the primary follicle grows. Acquisition of a

zona pellucida by the oocyte and the presence of several layers of surrounding cuboidal granulosa cells mark the development of secondary

follicles. It is at this stage that granulosa cells develop follicle-stimulating

hormone (FSH), estradiol, and androgen receptors and communicate

with one another through the development of gap junctions.

Bidirectional signaling between the germ cells and the somatic

cells in the ovary is a necessary component underlying the maturation

of the oocyte and the capacity for hormone secretion. For example,

oocyte-derived growth differentiation factor 9 (GDF-9) and bone morphogenic protein-15 (BMP-15), also known as GDF-9b, are required

for migration of pregranulosa and pretheca cells to the outer surface

of the developing follicle and, hence, initial follicle formation. GDF-9

is also required for formation of secondary follicles, as are granulosa

cell–derived KIT ligand (KITL) and the forkhead transcription factor

(FOXL2). A significant number of genes have been identified that are

required for development of the normal complement of oogonia in

the ovary, initial follicle development, and resistance to follicle loss;

all are candidates for premature ovarian insufficiency (POI), and

mutations in >50 genes have been identified in patients with POI,

with even more that have been associated with an earlier age at natural

menopause.

Antral follicles

Oogonia

Genital

ridge

Prophase of first

meiotic division

Granulosa

cells

Theca

cells

1° Oocytes

Primordial

follicles

Secondary

follicles

Resumption

of meiosis

Corpus

Mature luteum

oocyte

Preovulatory

follicles

Migratory

germ cells

Gonadotropin

independent

Gonadotropin

dependent

Ovulation

LH

FSH

FSH

LH

LH

FIGURE 392-1 Stages of ovarian development from the arrival of the migratory germ cells at the genital ridge through

gonadotropin-independent and gonadotropin-dependent phases that ultimately result in ovulation of a mature oocyte.

FSH, follicle-stimulating hormone; LH, luteinizing hormone.

3028 PART 12 Endocrinology and Metabolism

large number of FSH receptors, high aromatase activity, and elevated

concentrations of estradiol and inhibin A in follicular fluid. In addition, secretion of estradiol and inhibin from the dominant follicle

inhibits FSH and the growth of other follicles.

The dominant follicle undergoes rapid expansion during the 5–6 days

prior to ovulation, reflecting granulosa cell proliferation and accumulation of follicular fluid. FSH induces LH receptors on the granulosa

cells, and the preovulatory, or Graafian, follicle moves to the outer

ovarian surface in preparation for ovulation. The LH surge triggers the

resumption of meiosis, the suppression of granulosa cell proliferation,

and the induction of cyclooxygenase 2 (COX-2), prostaglandins, the

progesterone receptor (PR), and the epidermal growth factor (EGF)-

like growth factors amphiregulin, epiregulin, betacellulin, and neuroregulin 1, all of which are required for ovulation. Ovulation requires

production of extracellular matrix, leading to expansion of the cumulus

cell population that surrounds the oocyte and the controlled expulsion

of the egg and follicular fluid. Both progesterone and prostaglandins

(induced by the ovulatory stimulus) are essential for this process, as are

members of the matrix metalloproteinase family. After ovulation, luteinization of theca and granulosa cells is induced by LH in conjunction

with the acquisition of a rich vascular network in response to VEGF

and basic fibroblast growth factor (FGF). Traditional regulators of central reproductive control, gonadotropin-releasing hormone (GnRH)

and its receptor (GnRHR), as well as kisspeptin, are also produced in

the ovary and may be involved in corpus luteum function.

REGULATION OF OVARIAN FUNCTION

■ HYPOTHALAMIC AND PITUITARY SECRETION

GnRH neurons derive from cells in the olfactory placode and, to a lesser

extent, the neural crest. They migrate along the scaffold of the olfactory neurons across the cribriform plate to the hypothalamus where

they separate from the olfactory neurons. Studies in GnRH-deficient

patients who fail to undergo puberty have provided insights into genes

that control the ontogeny and function of GnRH neurons (Fig. 392-4).

KAL1, FGF8/FGFR1, PROK2/PROKR2, NSMF, HS6SD1, and CDH7,

among others (Chap. 391), have been implicated in the migration of

GnRH neurons to the hypothalamus while KISS, TAC3, Dyn and their

receptors are involved in the upstream regulation of GnRH secretion.

Approximately 7000 GnRH neurons, scattered throughout the medial

basal hypothalamus, establish contacts with capillaries of the pituitary

portal system in the median eminence. GnRH is secreted into the pituitary portal system in discrete pulses to stimulate synthesis and secretion of LH and FSH from pituitary gonadotropes, which comprise ~10%

of cells in the pituitary (Chap. 378). Functional connections of GnRH

neurons with the portal system are established by the end of the first

trimester, coinciding with the production of pituitary gonadotropins.

Thus, like the ovary, the hypothalamic and pituitary components of the

reproductive system are present before birth. However, the high levels of

estradiol and progesterone produced by the placenta suppress hypothalamic-pituitary stimulation of ovarian hormonal secretion in the fetus.

After birth and the loss of placenta-derived steroids, gonadotropin

levels rise. FSH levels are much higher in girls than in boys. This rise

in FSH results in circulating estradiol and increased inhibin B, but

without terminal follicle maturation or ovulation. Studies that have

identified mutations in TAC3, which encodes neurokinin B, and its

receptor, TAC3R, in patients with GnRH deficiency indicate that both

are involved in control of GnRH secretion and may be particularly

important at this early stage of development. By 12–20 months of age,

the reproductive axis is again suppressed, and a period of relative quiescence persists until puberty (Fig. 392-5). At the onset of puberty,

pulsatile GnRH secretion induces pituitary gonadotropin production.

In the early stages of puberty, LH and FSH secretion are apparent only

during sleep, but as puberty develops, pulsatile LH secretion occurs

throughout the day and night.

The mechanisms responsible for the childhood quiescence and

pubertal reactivation of the reproductive axis remain incompletely

understood. GnRH neurons in the hypothalamus respond to both

excitatory and inhibitory factors. Increased sensitivity to the inhibitory

2 m 5 m Birth Menarche Menopause

Migratory germ cells

Oogonia

Primary oocytes

4 × 105

2 × 106

7 × 106

FIGURE 392-2 Ovarian germ cell number is maximal at mid-gestation and decreases

precipitously thereafter.

FIGURE 392-3 Development of ovarian follicles. The Graafian follicle is also known

as a tertiary or preovulatory follicle. (Courtesy of JH Eichhorn and D Roberts,

Massachusetts General Hospital; with permission.)

DEVELOPMENT OF A MATURE FOLLICLE

The early stages of follicle growth are primarily driven by intraovarian

factors. Further maturation to the preovulatory stage, including the

resumption of meiosis in the oocyte, requires the combined stimulus

of FSH and luteinizing hormone (LH) (Fig. 392-1). Recruitment of

secondary follicles from the resting follicle pool requires the direct

action of FSH, whereas anti-müllerian hormone (AMH) produced

from small growing follicles (preantral) restrains this effect of FSH,

controlling the number of follicles entering the actively growing pool.

Accumulation of follicular fluid between the layers of granulosa cells

creates an antrum that divides the granulosa cells into two functionally

distinct groups: mural cells that line the follicle wall and cumulus cells

that surround the oocyte (Fig. 392-3). In addition to its role in normal

development of the müllerian system, the WNT signaling pathway is

required for normal antral follicle development and may also play a

role in ovarian steroidogenesis. Recruitment to the small antral stage

generally occurs over several cycles with further growth to follicle sizes

of >4–7 mm in waves during a single cycle. A single dominant follicle

emerges from the growing follicle pool within the first 5–7 days after

the onset of menses while the majority of follicles fall off their growth

trajectory and become atretic. Autocrine actions of activin and BMP6, derived from the granulosa cells, and paracrine actions of GDF-9,

BMP-15, BMP-6, and Gpr149, derived from the oocyte, are involved

in granulosa cell proliferation and modulation of FSH responsiveness.

Differential exposure to these factors, and to vascular endothelial

growth factor (VEGF), can alter vascular density and permeability,

likely explaining the mechanism whereby a given follicle is selected for

continued growth to the preovulatory stage. The dominant follicle can

be distinguished by its size, evidence of granulosa cell proliferation,

3029 Disorders of the Female Reproductive System CHAPTER 392

influence of gonadal steroids has long been implicated in the inhibition of GnRH secretion during childhood but has not been definitively

established in the human. Metabolic signals, including adipocyte-derived leptin, play a permissive role in reproductive function (Chap.

401). Studies of patients with isolated GnRH deficiency reveal that

mutations in the G protein–coupled receptor 54 (GPR54) gene (now

known as KISS1R) preclude the onset of puberty. The ligand for this

receptor is derived from the parent peptide, kisspeptin-1 (KISS1),

and is a powerful stimulant for GnRH release. A potential role for

kisspeptin in the onset of puberty has been suggested by upregulation

of KISS1 and KISS1R transcripts in the hypothalamus at the time of

puberty. TAC3, which stimulates GnRH secretion through kisspeptin

signaling, and dynorphin (Dyn), which plays an inhibitory role in

GnRH control, are frequently co-expressed with KISS1 in KNDY neurons of the median eminence that project to GnRH neurons. This system is intimately involved in both estrogen and progesterone negative

feedback regulation of GnRH secretion.

RFamide-related peptides (RFRPs) are the mammalian orthologues

of gonadotropin inhibitory hormone (GnIH), which was initially discovered in the quail. While RFRP-1 and RFRP-3 neurons send axonal

projections to GnRH neurons in humans and RFRPs are secreted into

the pituitary portal system, further studies are required to determine

their potential physiologic role in the human.

■ OVARIAN STEROIDS

Ovarian steroid-producing cells do not store hormones but produce

them in response to FSH and LH during the normal menstrual cycle.

The sequence of steps and the enzymes involved in the synthesis of

steroid hormones are similar in the ovary, adrenal, and testis. However,

the enzymes required to catalyze specific steps are compartmentalized

and may not be abundant or even present in all cell types. Within the

developing ovarian follicle, estrogen synthesis from cholesterol requires

close integration between theca and granulosa cells—sometimes called

the two-cell model for steroidogenesis (Fig. 392-6). FSH receptors are

confined to the granulosa cells, whereas LH receptors are restricted

to the theca cells until the late stages of follicular development, when

they are also found on granulosa cells. The theca cells surrounding the

follicle are highly vascularized and use cholesterol, derived primarily

from circulating lipoproteins, as the starting point for the synthesis

of androstenedione and testosterone under the control of LH. These

steroid precursors cross the basal lamina to the granulosa cells, which

receive no direct blood supply. The mural granulosa cells are particularly rich in aromatase and, under the control of FSH, produce

estradiol, the primary steroid secreted from the follicular phase ovary

and the most potent estrogen. Theca cell–produced androstenedione

and, to a lesser extent, testosterone are also secreted into peripheral

blood, where they can be converted to dihydrotestosterone in skin and

to estrogens in adipose tissue. The hilar interstitial cells of the ovary

are functionally similar to Leydig cells and are also capable of secreting

androgens. Stromal cells proliferate in response to androgens (as in

polycystic ovary syndrome [PCOS]) but do not secrete androgens.

However, high levels of androgens may be produced by luteinized theca

cells in women with hyperthecosis.

Development of the rich capillary network following rupture of the

follicle at the time of ovulation makes it possible for large molecules

such as low-density lipoprotein (LDL) to reach the luteinized granulosa

and theca lutein cells. As in the follicle, both cell types are required for

steroidogenesis in the corpus luteum. The luteinized granulosa cells

are the main source of progesterone production, whereas the smaller

theca lutein cells produce 17-hydroxyprogesterone and androgenic

substrates for aromatization to estradiol by the luteinized granulosa

cells. Production of estrogen metabolites by the corpus luteum plays

a significant role in maintenance of the vascularization required for

its function. LH is critical for formation and maintenance of corpus

luteum structure and function. LH and human chorionic gonadotropin (hCG) bind to a common receptor; thus, in conception cycles,

hCG produced upon fertilization rescues the declining function of the

Olfactory placode

Neural crest

Pituitary

GnRHR

KNDY

Migration Function

GnRH1

Hypothalamus

KISS1R

KISS1R

FIGURE 392-4 Genetic studies in patients with congenital forms of hypogonadotropic

hypogonadism have expanded our understanding of the development and migration

of gonadotropin-releasing hormone (GnRH) neurons from the olfactory placode

and neural crest to the hypothalamus as well as the upstream regulation of GnRH

secretion by kisspeptin (KISS1), neurokinin B (TAC3) and dynorphin (Dyn) which are

co-expressed in the KNDY neurons.

50 yr

Menopause

10–14 yr

Puberty reproductive years

FSH

Infancy Childhood

Birth−20 mo.

LH

Plasma gonadotropins

FIGURE 392-5 Follicle-stimulating hormone (FSH) and luteinizing hormone (LH)

are increased during the neonatal years but go through a period of childhood

quiescence before increasing again during puberty. Gonadotropin levels are cyclic

during the reproductive years and increase dramatically with the loss of negative

feedback that accompanies menopause.

Theca cell

Granulosa cell

Cholesterol

Androstenedione

Testosterone

Estrone

Estradiol

Androstenedione

Testosterone

aromatase

17βHSD

17,20 lyase

17 hydroxylase

3βHSD

17-OHP

progesterone

pregnenolone

LH

FSH

FIGURE 392-6 Estrogen production in the ovary requires the cooperative function

of the theca and granulosa cells under the control of luteinizing hormone (LH) and

follicle-stimulating hormone (FSH). HSD, hydroxysteroid dehydrogenase; OHP,

hydroxyprogesterone.

3030 PART 12 Endocrinology and Metabolism

corpus luteum, maintaining steroid and peptide secretion for the

first 10 weeks of pregnancy. hCG is commonly used for luteal phase

support in the treatment of infertility.

Steroid Hormone Actions Both estrogen and progesterone play

critical roles in the expression of secondary sexual characteristics in

women (Chap. 377). Estrogen promotes development of the ductule

system in the breast, whereas progesterone is responsible for glandular

development. In the reproductive tract, estrogens create a receptive

environment for fertilization and support pregnancy and parturition

through carefully coordinated changes in the endometrium, thickening of the vaginal mucosa, thinning of the cervical mucus, and uterine

growth and contractions. Progesterone induces secretory activity in

the estrogen-primed endometrium, increases the viscosity of cervical

mucus, and inhibits uterine contractions. Both gonadal steroids play

critical roles in negative and positive feedback of gonadotropin secretion. Progesterone also increases basal body temperature, which is used

clinically as a marker of ovulation.

The vast majority of circulating estrogens and androgens are carried in the blood bound to carrier proteins, which restrain their free

diffusion into cells and prolong their clearance, serving as a reservoir.

High-affinity binding proteins include sex hormone–binding globulin

(SHBG), which binds androgens with somewhat greater affinity than

estrogens, and corticosteroid-binding globulin (CBG), which also

binds progesterone. Modulations in binding protein levels by insulin,

androgens, and estrogens contribute to high bioavailable testosterone

levels in PCOS and to high circulating total estrogen and progesterone

levels during pregnancy.

Estrogens act primarily through binding to the nuclear receptors,

estrogen receptor (ER) α and β. Transcriptional coactivators and

co-repressors modulate ER action (Chap. 377). Both ER subtypes are

present in the hypothalamus, pituitary, ovary, and reproductive tract.

Although ERα and β exhibit some functional redundancy, there is also

a high degree of specificity, particularly in expression within cell types.

For example, ERα functions in ovarian theca cells, whereas ERβ is critical

for granulosa cell function. There is also evidence for membrane-initiated

signaling by estrogen. Similar signaling mechanisms pertain for progesterone with evidence of transcriptional regulation through PR A and B

protein isoforms, as well as rapid membrane signaling.

■ OVARIAN PEPTIDES

Inhibin was initially isolated from gonadal fluids based on its ability

to selectively inhibit FSH secretion from pituitary cells. Inhibin is a

heterodimer composed of an α subunit and a βA or βB subunit to form

inhibin A or inhibin B, both of which are secreted from the ovary.

Activin is a homodimer of inhibin β subunits with the capacity to

stimulate the synthesis and secretion of FSH. Inhibins and activins are

members of the transforming growth factor β (TGF-β) superfamily of

growth and differentiation factors. During the purification of inhibin,

follistatin, an unrelated monomeric protein that inhibits FSH secretion,

was discovered. Within the pituitary, follistatin inhibits FSH secretion

indirectly by binding and neutralizing activin.

Inhibin B is constitutively secreted from the granulosa cells of

small antral follicles, and its serum levels increase in conjunction with

granulosa cell proliferation during recruitment of secondary follicles

under the control of FSH. Inhibin B is an important inhibitor of FSH,

independent of estradiol, during the menstrual cycle. Inhibin A is present in both granulosa and theca cells and is secreted by the dominant

follicle. Inhibin A is also present in luteinized granulosa cells and is a

major secretory product of the corpus luteum. Synthesis and secretion

of inhibin A are directly controlled by FSH and LH. Although activin is

also secreted from the ovary, the excess of follistatin in serum, combined

with its nearly irreversible binding of activin, make it unlikely that ovarian activin plays an endocrine role in FSH regulation. However, there

is evidence that activin plays an autocrine/paracrine role in the ovary,

in addition to its intrapituitary role in modulation of FSH production.

AMH (also known as müllerian-inhibiting substance) is important

in ovarian biology in addition to the function from which it derived

its name (i.e., promotion of the degeneration of the müllerian system

during embryogenesis in the male). AMH is produced by granulosa

cells from small preantral and early antral follicles and is a marker of

ovarian reserve with advantages over inhibin B because of its relative

stability across the menstrual cycle. AMH inhibits the recruitment of

primordial follicles into the follicle pool and counters FSH stimulation

of aromatase expression. AMH levels are highest in the early twenties

and decrease markedly by menopause. AMH is increased in PCOS in

conjunction with the abundance of small follicles in this disorder.

Gonadotropin surge attenuating factor (GnSAF) is an ovarian factor that attenuates GnRH-induced gonadotropin secretion. Its role is

not yet fully understood, but there is an inverse relationship between

GnSAF and follicle size, suggesting that its primary role involves the

early stages of follicle development rather than curtailing the gonadotropin surge as its name implies.

Relaxin is produced primarily by the theca lutein cells of the corpus

luteum. Both relaxin and its receptor, RXFP1, are highly expressed

in the uterus during the peri-implantation period in the marmoset,

and its primary role appears to be in promoting decidualization and

vascularization of the endometrium prior to implantation. Relaxin was

named for its ability to suppress myometrial contractility in pigs and

rodents, but it does not appear to exert this activity in women.

HORMONAL INTEGRATION OF THE

NORMAL MENSTRUAL CYCLE

The sequence of changes responsible for mature reproductive function

is coordinated through a series of negative and positive feedback loops

that alter pulsatile GnRH secretion, the pituitary response to GnRH,

and the relative secretion of LH and FSH from the gonadotrope. The

frequency and amplitude of pulsatile GnRH secretion differentially

modulate the synthesis and secretion of LH and FSH. Slow GnRH

pulse frequencies favor FSH synthesis, whereas increased GnRH pulse

frequency and amplitude favor LH synthesis. Activin is produced in

both pituitary gonadotropes and folliculostellate cells and stimulates

the synthesis and secretion of FSH through autocrine-paracrine mechanisms that are modulated by follistatin. Inhibins function as potent

antagonists of activins through sequestration of the activin receptors.

Although inhibin is expressed in the pituitary, gonadal inhibin is the

principal source of feedback inhibition of FSH.

For the majority of the cycle, the reproductive system functions in a

classic endocrine negative feedback mode. Estradiol and progesterone

inhibit GnRH secretion, acting through kisspeptin and dynorphin in

the KNDy neurons, while the inhibins act at the pituitary to selectively

inhibit FSH synthesis and secretion (Fig. 392-7). Estradiol also contributes to negative feedback at the pituitary with an effect that is greater

for FSH than LH. This tightly regulated negative feedback control of

FSH is critical for development of the single mature oocyte that characterizes normal reproductive function in women. In addition to these

negative feedback controls, the menstrual cycle is uniquely dependent

on estrogen-induced positive feedback to produce an LH surge that is

essential for ovulation of a mature follicle. Estrogen negative feedback

in women occurs primarily at the hypothalamus with a small pituitary

contribution, whereas estrogen positive feedback occurs at the pituitary

in women with upregulation of GnRH signaling and responsiveness. In

women, hypothalamic GnRH secretion plays a permissive role in generating the preovulatory gonadotropin surge, a mechanism that differs

significantly from that in rodents and other species that rely on seasonal

and circadian cues, in which a surge of GnRH also occurs.

■ THE FOLLICULAR PHASE

The follicular phase is characterized by recruitment of a cohort of secondary follicles and the ultimate selection of a dominant preovulatory follicle

(Fig. 392-8). The follicular phase begins, by convention, on the first day

of menses. However, follicle recruitment is initiated by the rise in FSH that

begins in the late luteal phase of the previous cycle in conjunction with

the loss of negative feedback of gonadal steroids and likely inhibin A. The

fact that a 20–30% increase in FSH is adequate for follicular recruitment

speaks to the marked sensitivity of the resting follicle pool to FSH. The

resultant granulosa cell proliferation is responsible for increasing early

follicular phase levels of inhibin B. Inhibin B, in conjunction with rising

3031 Disorders of the Female Reproductive System CHAPTER 392

levels of estradiol and inhibin A, restrains FSH secretion during this

critical period such that only a single follicle matures in the vast majority

of cycles. The increased risk of multiple gestation associated with the

increased levels of FSH characteristic of advanced maternal age or with

exogenous gonadotropin administration in the treatment of infertility

attests to the importance of negative feedback regulation of FSH. With

further growth of the dominant follicle, estradiol and inhibin A increase

and the follicle acquires LH receptors. Increasing levels of estradiol are

responsible for proliferative changes in the endometrium. The exponential rise in estradiol results in positive feedback on the pituitary, leading to

the generation of an LH surge (and a smaller FSH surge), thereby triggering ovulation and luteinization of granulosa and theca cells.

■ THE LUTEAL PHASE

The luteal phase begins with the formation of the corpus luteum

from the ruptured follicle (Fig. 392-8). Progesterone and inhibin A

are produced from the luteinized granulosa cells, which continue to

aromatize theca-derived androgen precursors, producing estradiol.

The combined actions of estrogen and progesterone are responsible

for the secretory changes in the endometrium that are necessary for

implantation. The corpus luteum is supported by LH but has a finite

life span because of diminished sensitivity to LH. The demise of the

corpus luteum results in a progressive decline in hormonal support of

the endometrium. Inflammation or local hypoxia and ischemia result

in vascular changes in the endometrium, leading to the release of

cytokines, cell death, and shedding of the endometrium.

If conception occurs, hCG produced by the trophoblast binds to LH

receptors on the corpus luteum, maintaining steroid hormone production and preventing involution of the corpus luteum until its hormonal

function is taken over by the placenta 6–10 weeks after conception.

CLINICAL ASSESSMENT OF OVARIAN

FUNCTION

Menstrual bleeding should become regular within 2–4 years of menarche, although anovulatory and irregular cycles are common before that.

For the remainder of adult reproductive life, the cycle length counted

from the first day of menses to the day preceding subsequent menses is

~28 days, with a range of 25–35 days. However, cycle-to-cycle variability for an individual woman is ±2 days. Luteal phase length is relatively

constant between 12 and 14 days in normal cycles; thus, the major

variability in cycle length is due to variations in follicular phase length.

The duration of menstrual bleeding in ovulatory cycles varies between

4 and 6 days. There is a gradual shortening of cycle length with age

such that women aged >35 years have cycles that are shorter than

during their younger reproductive years. Anovulatory cycles increase

as women approach menopause, and bleeding patterns may be erratic.

Women who report regular monthly bleeding generally have ovulatory cycles, but several other clinical signs can be used to assess

the likelihood of ovulation. Some women experience mittelschmerz,

described as midcycle pelvic discomfort that is thought to be caused

by the rapid expansion of the dominant follicle at the time of ovulation. A constellation of premenstrual moliminal symptoms such as

bloating, breast tenderness, mood changes, and food cravings often

occur several days before menses in ovulatory cycles, but their absence

cannot be used as evidence of anovulation. Methods that can be used

to determine whether ovulation occurred include a serum progesterone level >3 ng/mL ~7 days after ovulation, an increase in basal body

temperature of 0.24°C (>0.5°F) in the second half of the cycle due to

the thermoregulatory effect of progesterone, or detection of the urinary

LH surge using ovulation predictor kits. Because ovulation occurs ~36 h

after the LH surge, urinary LH can be helpful in timing intercourse to

coincide with ovulation.

Ultrasound can be used to detect the growth of the fluid-filled

antrum of the developing follicle and to assess endometrial thickness

in response to increasing estradiol levels in the follicular phase. It can

also be used to provide evidence of ovulation by documenting collapse

of the dominant follicle and/or the presence of a corpus luteum as well

as the characteristic echogenicity of the secretory endometrium of the

luteal phase.

PUBERTY

■ NORMAL PUBERTAL DEVELOPMENT IN GIRLS

The first menstrual period (menarche) occurs relatively late in the

series of developmental milestones that characterize normal pubertal

development (Table 392-1). Menarche is preceded by the appearance

of pubic and then axillary hair (adrenarche) as a result of maturation of

the zona reticularis in the adrenal gland and increased adrenal androgen secretion, particularly dehydroepiandrosterone (DHEA). The triggers for adrenarche remain unknown but may involve increases in body

mass index, as well as in utero and neonatal factors. Menarche is also

preceded by breast development (thelarche). The breast is exquisitely

sensitive to the very low levels of estrogen that result from peripheral

conversion of adrenal androgens and the low levels of estrogen secreted

GnRH

KNDY neurons

FSH

LH

Negative Feedback Positive Feedback

+ ++

–

++ –

Estradiol

Progesterone

Estradiol

Inhibin B

Inhibin A

Estradiol

FIGURE 392-7 The reproductive system in women is critically dependent on both

negative feedback of gonadal steroids and inhibin to modulate follicle-stimulating

hormone (FSH) secretion and on estrogen positive feedback to generate the

preovulatory luteinizing hormone (LH) surge. GnRH, gonadotropin-releasing hormone.

Follicular

phase

Luteal

phase

Secondary Antral

Ovarian follicles

FSH

LH

Inhibin B

Proliferative Secretory

Inhibin A

E2

Prog

Endo

Dominant Ovulation Corpus

luteum

Corpus

albicans

FIGURE 392-8 Relationship between gonadotropins, follicle development,

gonadal secretion, and endometrial changes during the normal menstrual cycle.

E2

, estradiol; Endo, endometrium; FSH, follicle-stimulating hormone; LH, luteinizing

hormone; Prog, progesterone.

TABLE 392-1 Mean Age (Years) of Pubertal Milestones in Girls

ONSET OF

BREAST/

PUBIC HAIR

DEVELOPMENT

AGE OF

PEAK

HEIGHT

VELOCITY MENARCHE

FINAL

BREAST/

PUBIC HAIR

DEVELOPMENT

ADULT

HEIGHT

White 10.2 11.9 12.6 14.3 17.1

Black 9.6 11.5 12 13.6 16.5

Source: Adapted with permission from FM Biro et al: Pubertal correlates in black

and white girls. J Pediatr 148:234, 2006.

3032 PART 12 Endocrinology and Metabolism

from the ovary early in pubertal maturation. This estrogen sensitivity

also explains why infants occasionally develop breast tissue in response

to exogenous or environmental estrogens. Breast development precedes the appearance of pubic and axillary hair in ~60% of girls.

The interval between the onset of breast development and menarche is

~2 years. There has been a gradual decline in the age of menarche over

the past century, attributed in large part to improvement in nutrition,

and there is a relationship between adiposity and earlier sexual maturation in girls. In the United States, menarche occurs at an average age

of 12.5 years (Table 392-1).

Much of the variation in the timing of puberty is due to genetic

factors. Heritability estimates from twin studies range between 50 and

80%. Adrenarche and thelarche occur ~1 year earlier in black girls

compared with white girls, although the difference in the timing of

menarche is less pronounced. Genome-wide association studies have

identified over a hundred genes associated with pubertal timing in boys

and girls attesting to the high degree of coordination of this reproductive

and growth milestone. These findings include genes involved in GnRH

secretion (e.g., TACR3, and the maternally imprinted gene, MKRN3, that

has been associated with familial precocious puberty), pituitary development and function (e.g., POU1F1), hormone synthesis and bioactivity

(e.g., STARD4, ESR1, RXRG), gonadal feedback (e.g., INHBA, ESR1), and

energy homeostasis and growth, including LIN28B, a sentinel puberty

gene, which is a potent regulator of microRNA processing.

Other important hormonal changes also occur in conjunction with

puberty. Growth hormone (GH) levels increase early in puberty, stimulated in part by the pubertal increase in estrogen secretion. GH increases

insulin-like growth factor-1 (IGF-1), which enhances linear growth. The

growth spurt is generally less pronounced in girls than in boys, with a

peak growth velocity of ~7 cm/year. Linear growth is ultimately limited

by closure of epiphyses in the long bones as a result of prolonged exposure to estrogen. Puberty is also associated with mild insulin resistance.

■ DISORDERS OF PUBERTY

The differential diagnosis of precocious and delayed puberty is similar

in boys (Chap. 391) and girls. However, there are differences in the

timing of normal puberty and differences in the relative frequency of

specific disorders in girls compared with boys.

Precocious Puberty Traditionally, precocious puberty has been

defined as the development of secondary sexual characteristics before

the age of 8 in girls based on data from Marshall and Tanner in British

girls studied in the 1960s. More recent studies led to recommendations

that girls be evaluated for precocious puberty if breast development or

pubic hair is present at <7 years of age for white girls or <6 years for

black girls; however, these guidelines have not been widely accepted in

favor of careful follow-up in girls presenting at <8 years.

Precocious puberty in girls is most often centrally mediated

(Table 392-2), resulting from early activation of the hypothalamicpituitary-ovarian axis. It is characterized by pulsatile LH secretion

(which is initially associated with deep sleep) and an enhanced LH and

FSH response to exogenous GnRH or a GnRH agonist (two- to threefold

stimulation) (Table 392-3). True precocity is marked by advancement

in bone age of >2 standard deviations, a recent history of growth acceleration, and progression of secondary sexual characteristics. In girls,

centrally mediated precocious puberty (CPP) is idiopathic in ~85% of

cases; however, neurogenic causes must be considered. Activating mutations in KISS, KISS1, and KISS1R have been found in a small number of

patients with CPP, and loss-of-function mutations in MKRN3 have been

reported in familial CPP. However, the frequency of these mutations is

insufficient to justify their use in routine clinical testing. GnRH agonists

that induce pituitary desensitization are the mainstay of treatment to

prevent premature epiphyseal closure and preserve adult height, as well

as to manage psychosocial repercussions of precocious puberty.

Peripherally mediated precocious puberty does not involve activation of the hypothalamic-pituitary-ovarian axis and is characterized by

suppressed gonadotropins in the presence of elevated estradiol. Management of peripheral precocious puberty involves treating the underlying

disorder (Table 392-2) and limiting the effects of gonadal steroids using

aromatase inhibitors, inhibitors of steroidogenesis, and ER blockers.

It is important to be aware that central precocious puberty can also

develop in girls whose precocity was initially peripherally mediated, as

in McCune-Albright syndrome and congenital adrenal hyperplasia.

TABLE 392-2 Differential Diagnosis of Precocious Puberty

CENTRAL (GnRH DEPENDENT) PERIPHERAL (GnRH INDEPENDENT)

Idiopathic

CNS tumors

Hamartomas

Astrocytomas

Adenomyomas

Gliomas

Germinomas

CNS infection

Genetic, i.e., KISS1, KISS1R, MKRN3,

DLK1

Head trauma

Iatrogenic

Radiation

Chemotherapy

Surgical

CNS malformation

Arachnoid or suprasellar cysts

Septo-optic dysplasia

Hydrocephalus

Congenital adrenal hyperplasia

Estrogen-producing tumors

Adrenal tumors

Ovarian tumors

Gonadotropin/hCG-producing tumors

Exogenous exposure to estrogen or

androgen or lavender or tea-tree oil

McCune-Albright syndrome

Aromatase excess syndrome

Abbreviations: CNS, central nervous system; DLK1, delta-like 1 homolog gene;

GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin;

KISS1, kisspeptin gene; KISS1R, kisspeptin receptor gene; MKRN3, makorin ring

finger protein 3 gene.

TABLE 392-3 Evaluation of Precocious and Delayed Puberty

PRECOCIOUS DELAYED

Initial Screening Tests

History and physical × ×

Assessment of growth velocity × ×

Bone age × ×

LH, FSH × ×

Estradiol, testosterone × ×

DHEAS × ×

17-Hydroxyprogesterone ×

TSH, T4 × ×

Complete blood count ×

Sedimentation rate, C-reactive protein ×

Electrolytes, renal function ×

Liver enzymes ×

IGF-1, IGFBP-3 ×

Urinalysis ×

Secondary Tests

Pelvic ultrasound × ×

Cranial MRI × ×

β-hCG ×

GnRH/agonist stimulation test × ×

ACTH stimulation test ×

Inflammatory bowel disease panel × ×

Celiac disease panel ×

Prolactin ×

Karyotype ×

Abbreviations: ACTH, adrenocorticotropic hormone; DHEAS,

dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; GnRH,

gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; IGF-1,

insulin-like growth factor 1; IGFBP-3, IGF-binding protein 3; LH, luteinizing hormone;

MRI, magnetic resonance imaging; TSH, thyroid-stimulating hormone; T4

, thyroxine.