3033 Menstrual Disorders and Pelvic Pain CHAPTER 393

Incomplete and intermittent forms of precocious puberty may also

occur. For example, premature breast development may occur in girls

before the age of 2 years, with no further progression and without

significant advancement in bone age, estrogen production, or compromised height. Premature adrenarche can also occur in the absence of

progressive pubertal development, but it must be distinguished from

late-onset congenital adrenal hyperplasia and androgen-secreting

tumors, in which case it may be termed heterosexual precocity. Premature adrenarche may be associated with obesity, hyperinsulinemia, and

the subsequent predisposition to PCOS.

Delayed Puberty Delayed puberty (Table 392-4) is defined as the

absence of secondary sexual characteristics by age 13 in girls. The diagnostic considerations are very similar to those for primary amenorrhea

(Chap. 393). Between 25 and 40% of delayed puberty in girls is of ovarian origin, with Turner syndrome accounting for the majority of such

patients. Delayed puberty may occur in the setting of systemic illnesses,

including celiac disease and chronic renal disease, and endocrinopathies such as diabetes and hypothyroidism. In addition, girls appear to

be particularly susceptible to the adverse effects of decreased energy

balance resulting from exercise, dieting, and/or eating disorders, and

thus, functional hypothalamic amenorrhea (HA) can present with

primary amenorrhea. Together, these reversible conditions account

for ~25% of delayed puberty in girls. Congenital hypogonadotropic

hypogonadism in girls or boys can be caused by mutations in several

different genes or combinations of genes (Fig. 392-4, Chap. 391,

Table 392-2). Approximately 50% of girls with congenital hypogonadotropic hypogonadism, with or without anosmia, have a history of some

degree of breast development, and 10% report one to two episodes of

vaginal bleeding. Family studies suggest that genes identified in association with absent puberty may also cause delayed puberty, and recent

reports have further suggested that a genetic susceptibility to environmental stresses such as diet and exercise may account for at least some

cases of functional HA, including in girls who present with primary

amenorrhea. Although neuroanatomic causes of delayed puberty are

considerably less common in girls than in boys, it is always important

to rule these out in the setting of hypogonadotropic hypogonadism.

■ FURTHER READING

Bradley SH et al: Precocious puberty. BMJ 368:l6597, 2020.

Euster EA: Update on precocious puberty. J Pediatr Adolesc Gynecol

32:455, 2019.

George JT et al: Effect of gonadotropin-inhibitory hormone on

luteinizing hormone secretion in humans. Clin Endocrinol (Oxf)

86:731, 2017.

Kaplowitz P, Bloch C: The section on endocrinology. Evaluation

and referral of children with signs of early puberty. Pediatrics

137:e20153732, 2016.

Mishra GD et al: EMAS position statement: Predictors of premature

and early natural menopause. Maturitas 123:8, 2019.

Neocleous V et al: GnRH deficient patients with congenital hypogonadotropic hypogonadism: Novel genetic findings in ANOS1,

RNF216, WDR11, FGFR1, CHD7, and POLR3A genes in a case series

and review of the literature. Front Endocrinol (Lausanne) 11:626,

2020

Richards JS: The ovarian cycle. Vitam Horm 107:1, 2018.

Stamou MI et al: Discovering genes essential to the hypothalamic

regulation of human reproduction using a human disease model:

Adjusting to life in the “-omics” era. Endocr Rev 36:603, 2015.

Tucker EJ et al: Premature ovarian insufficiency: New perspectives on

genetic cause and phenotypic spectrum. Endocr Rev 37:609, 2016.

Willemsen RH, Dunger DB: Normal variation in pubertal timing:

Genetic determinants in relation to growth and adiposity. Endocr

Dev 29:17, 2016.

TABLE 392-4 Differential Diagnosis of Delayed Puberty

Hypergonadotropic

Ovarian

Turner’s syndrome

Gonadal dysgenesis

Chemotherapy/radiation therapy

Galactosemia

Autoimmune oophoritis

Congenital lipoid hyperplasia

Steroidogenic enzyme abnormalities

17α-Hydroxylase deficiency

Aromatase deficiency

Gonadotropin/receptor mutations

FSHβ, LHR, FSHR

Androgen resistance syndrome

Hypogonadotropic

Genetic

Hypothalamic syndromes

 Leptin/leptin receptor

 HESX1 (septo-optic dysplasia)

 PC1 (prohormone convertase)

IHH and Kallmann’s syndrome

 KAL1, FGF8, FGFR1, NSMF, PROK2, PROKR2, SEM3A, HS6ST1, WDR11, CHD7

 KISS1, KISS1R, TAC3, TAC3R, GnRH1, GnRHR, and others

Abnormalities of pituitary development/function

PROP1

CNS tumors/infiltrative disorders

Craniopharyngioma

Astrocytoma, germinoma, glioma

Prolactinomas, other pituitary tumors

Histiocytosis X

Chemotherapy/radiation

Functional

Chronic diseases

Malnutrition

Excessive exercise

Eating disorders

Abbreviations: CHD7, chromodomain-helicase-DNA-binding protein 7; CNS, central

nervous system; FGF8, fibroblast growth factor 8; FGFR1, fibroblast growth factor 1

receptor; FSHb, follicle-stimulating hormone β chain; FSHR, FSH receptor; GNRHR,

gonadotropin-releasing hormone receptor; HESX1, homeobox, embryonic stem

cell expressed 1; HS6ST1, heparin sulfate 6-O sulfotransferase 1; IHH, idiopathic

hypogonadotropic hypogonadism; KAL, Kallmann; KISS1, kisspeptin 1; KISSR1,

KISS1 receptor; LHR, luteinizing hormone receptor; NSMF, NMDA receptor

synaptonuclear signaling and neuronal migration factor; PROK2, prokineticin 2;

PROKR2, prokineticin receptor 2; PROP1, prophet of Pit1, paired-like homeodomain

transcription factor; SEMA3A, semaphorin-3A; WDR11, WD repeat-containing

protein 11.

Menstrual dysfunction can signal an underlying abnormality that may

have long-term health consequences. Although frequent or prolonged

bleeding usually prompts a woman to seek medical attention, infrequent or absent bleeding may seem less troubling, and the patient may

not bring it to the attention of the physician. Thus, a focused menstrual

history is a critical part of every encounter with a female patient. Pelvic pain is a common complaint that may relate to an abnormality of

the reproductive organs but also may be of gastrointestinal, urinary

393 Menstrual Disorders

and Pelvic Pain

Janet E. Hall, Anuja Dokras

3034 PART 12 Endocrinology and Metabolism

tract, or musculoskeletal origin. Depending on its cause, pelvic pain

may require urgent surgical attention. Recent guidelines no longer

recommend routine pelvic examination in asymptomatic, average-risk

women other than periodic cervical cancer screening. However, pelvic

examination is an important part of the evaluation of amenorrhea,

abnormal uterine bleeding, and pelvic pain.

MENSTRUAL DISORDERS

■ DEFINITION AND PREVALENCE

Amenorrhea refers to the absence of menstrual periods. Amenorrhea

is classified as primary if menstrual bleeding has never occurred in the

absence of hormonal treatment or secondary if menstrual periods cease

for 3–6 months. Primary amenorrhea is a rare disorder that occurs in

<1% of the female population. However, between 3 and 5% of women

experience at least 3 months of secondary amenorrhea in any specific

year. There is no evidence that race or ethnicity influences the prevalence of amenorrhea. However, because of the importance of adequate

nutrition for normal reproductive function, both the age at menarche

and the prevalence of secondary amenorrhea vary significantly in different parts of the world.

Oligomenorrhea is defined as a cycle length >35 days or <10 menses

per year. Both the frequency and the amount of vaginal bleeding are

irregular in oligomenorrhea, and moliminal symptoms (premenstrual

breast tenderness, food cravings, mood lability), suggestive of ovulation, are variably present. Anovulation can also present with intermenstrual intervals <24 days. Frequent or heavy irregular bleeding is

termed dysfunctional uterine bleeding if anatomic uterine and outflow

tract lesions or a bleeding diathesis have been excluded. Oligo- and

anovulation are most frequently associated with polycystic ovarian

syndrome (PCOS).

Primary Amenorrhea The absence of menarche (the first menstrual period) by age 16 has been used traditionally to define primary

amenorrhea. However, other factors, such as growth, secondary sexual

characteristics, and the presence of cyclic pelvic pain, also influence

the age at which primary amenorrhea should be

investigated. Recent studies suggest that puberty

is occurring at an earlier age, particularly in

obese girls. However, it is important to note that

these data reflect earlier breast development

alone with minimal change in the age of menarche. Thus, an evaluation for amenorrhea should

be initiated by age 15 or 16 in the presence of

normal growth and secondary sexual characteristics; age 13 in the absence of secondary sexual

characteristics or if height is less than the third

percentile; age 12 or 13 in the presence of breast

development and cyclic pelvic pain; or within 2

years of breast development if menarche has not

occurred.

Secondary Amenorrhea or Oligomenor- rhea Irregular cycles are relatively common

for up to 3 years after menarche and for 1–2

years before the final menstrual period. In the

intervening years, menstrual cycle length is ~28

days, with an intermenstrual interval normally

ranging between 25 and 35 days. Cycle-tocycle variability in an individual woman who is

ovulating consistently is generally +/− 2 days.

Pregnancy is the most common cause of amenorrhea and should be excluded early in any

evaluation of menstrual irregularity. However,

many women occasionally miss a single period.

Three months of secondary amenorrhea, or

6 months in women with previously irregular

cycles, should prompt an evaluation, as should

a history of intermenstrual intervals >35 or <21

days or bleeding that persists for >7 days.

Hypothalamus 28% 36%

Pituitary 2% 15%

PCOS 8% 30%

Ovary 43% 12%

Uterus/outflow tract 19% 7%

Primary Secondary

GnRH

LH

Estradiol

Progesterone

FSH

–

–

+

Inhibin B

Inhibin A

Estradiol

FIGURE 393-1 Role of the hypothalamic-pituitary-gonadal axis in the etiology of amenorrhea. Gonadotropinreleasing hormone (GnRH) secretion from the hypothalamus stimulates follicle-stimulating hormone (FSH) and

luteinizing hormone (LH) secretion from the pituitary to induce ovarian folliculogenesis and steroidogenesis.

Ovarian secretion of estradiol and progesterone controls the shedding of the endometrium, resulting in

menses, and, in combination with the inhibins, provides feedback regulation of the hypothalamus and pituitary

to control secretion of FSH and LH. The prevalence of amenorrhea resulting from abnormalities at each level

of the reproductive system (hypothalamus, pituitary, ovary, uterus, and outflow tract) varies depending on

whether amenorrhea is primary or secondary. PCOS, polycystic ovarian syndrome.

■ DIAGNOSIS

Pregnancy is the most common cause of amenorrhea and must be

excluded in all cases, regardless of patient history. Evaluation of menstrual dysfunction depends on understanding the interrelationships

between the four critical components of the reproductive tract: (1) the

hypothalamus, (2) the pituitary, (3) the ovaries, and (4) the uterus and

outflow tract (Fig. 393-1; Chap. 392). This system is maintained by

complex negative and positive feedback loops involving the ovarian

steroids (estradiol and progesterone) and peptides (inhibin B and

inhibin A) and the hypothalamic (gonadotropin-releasing hormone

[GnRH]) and pituitary (follicle-stimulating hormone [FSH] and

luteinizing hormone [LH]) components of this system (Fig. 393-1).

Disorders of menstrual function can be thought of in two main

categories: disorders of the uterus and outflow tract and disorders of

ovulation. Many of the conditions that cause primary amenorrhea are

congenital but go unrecognized until the time of normal puberty (e.g.,

genetic, chromosomal, and anatomic abnormalities). All causes of secondary amenorrhea also can cause primary amenorrhea.

Disorders of the Uterus or Outflow Tract Abnormalities

of the uterus and outflow tract typically present as primary amenorrhea. In patients with normal pubertal development and a blind

vagina, the differential diagnosis includes obstruction by a transverse vaginal septum or imperforate hymen; müllerian agenesis

(Mayer-Rokitansky-Kuster-Hauser syndrome), which can be caused

by mutations in the WNT4 gene, and androgen insensitivity syndrome

(AIS), which is an X-linked recessive disorder that accounts for ~10%

of all cases of primary amenorrhea (Chap. 391). Patients with AIS

have a 46,XY karyotype, but because of the lack of androgen receptor

responsiveness, those with complete AIS lack features of androgenization and have female external genitalia. The absence of pubic and

axillary hair distinguishes them clinically from patients with müllerian

agenesis, as does a testosterone level in the male range. The rare patient

with 5α reductase type 2 enzyme deficiency has a similar presentation

but undergoes virilization at the time of puberty. Asherman’s syndrome

3035 Menstrual Disorders and Pelvic Pain CHAPTER 393

presents as secondary amenorrhea or hypomenorrhea and results

from partial or complete obliteration of the uterine cavity by adhesions that prevent normal growth and shedding of the endometrium.

Curettage performed for pregnancy complications accounts for >90%

of cases; genital tuberculosis is an important cause in regions where it

is endemic.

TREATMENT

Disorders of the Uterus or Outflow Tract

Obstruction of the outflow tract usually presents as dysmenorrhea

or lower abdominal cyclic pain with no menses. Evaluation of the

patient includes a medical history, physical examination including

a perineal examination, and ultrasound imaging. In some cases, an

MRI can more accurately identify the reproductive tract anomaly

prior to surgery. It is important that surgery be performed as soon

as the diagnosis is made as the risk of endometriosis is increased

with retrograde menstrual flow. Müllerian agenesis may require

surgical intervention to allow sexual intercourse, although vaginal

dilatation is adequate in some patients. Because ovarian function

is normal, assisted reproductive techniques can be used with a

surrogate carrier. More recently, there have been a few cases of

successful uterine transplantation in women with müllerian agenesis. AIS (Chap. 390) requires gonadectomy because there is risk

of gonadoblastoma in the dysgenetic gonads, although surgery is

generally delayed until after breast development and the pubertal

growth spurt. Estrogen replacement is indicated after gonadectomy,

and vaginal dilatation may be required to allow sexual intercourse.

Disorders of Ovulation Once uterus and outflow tract abnormalities have been excluded, other causes of amenorrhea involve disorders

of ovulation. The differential diagnosis is based on the results of initial

tests, including a pregnancy test, an FSH level (to determine whether

the cause is likely to be ovarian or central), and assessment of hyperandrogenism (Fig. 393-2).

HYPOGONADOTROPIC HYPOGONADISM Low estrogen levels in combination with normal or low levels of LH and FSH are seen with

anatomic, genetic, or functional abnormalities that interfere with hypothalamic GnRH secretion or normal pituitary responsiveness to GnRH.

Although relatively uncommon, tumors and infiltrative diseases should

be considered in the differential diagnosis of hypogonadotropic hypogonadism (Chap. 380). These disorders may present with primary

or secondary amenorrhea. They may occur in association with other

features suggestive of hypothalamic or pituitary dysfunction, such as

short stature, diabetes insipidus, galactorrhea, and headache. Hypogonadotropic hypogonadism also may be seen after cranial irradiation.

In the postpartum period, amenorrhea occurs normally in association

with breast feeding but may also be caused by pituitary necrosis (Sheehan’s syndrome) or lymphocytic hypophysitis. Because reproductive

dysfunction is commonly associated with hyperprolactinemia from

neuroanatomic lesions or medications, prolactin should be measured

in all patients with hypogonadotropic hypogonadism (Chap. 380).

Isolated hypogonadotropic hypogonadism (IHH) occurs in women,

although it is three times more common in men. IHH generally

presents with primary amenorrhea, although 50% have some degree

of breast development, and ~10% report one to two menses. IHH

is associated with anosmia in half of women (termed Kallmann’s

syndrome). Genetic causes of IHH have been identified in ~50% of

patients (Chaps. 391 and 392).

Functional hypothalamic amenorrhea (HA) is a diagnosis of exclusion of other causes of hypogonadotropic hypogonadism including

chronic diseases (type 1 diabetes, celiac disease, hyperthyroidism,

Cushing’s syndrome) and use of opioids, glucocorticoids, or psychotropic medications that increase prolactin levels. Functional HA is most

commonly associated with conditions causing a mismatch between

energy expenditure and energy intake and/or significant stress. Variants in genes associated with IHH may increase susceptibility to these

environmental inputs, accounting in part for the clinical variability in

this disorder. Metabolic and stress signaling is transduced to the reproductive axis, at least in part, through leptin signaling from the periphery and via hypothalamic kisspeptin control of GnRH. The diagnosis

Pituitary

causes

Hypothalamic

causes

Hyperandrogenism

↑ testosterone

hirsutism, acne

R/o

• 21 hydroxylase

 deficiency

• Tumor

• High

 premature

ovarian

 insufficiency

• Turner’s

 syndrome

• Androgen

 insensitivity

 syndrome

• 5α reductase

 deficiency

• Müllerian

 agenesis

• Imperforate

 hymen

• Transverse

 vaginal

 septum

• Cervical

 stenosis

History of

uterine

instrumentation

Normal prolactin

FSH negative

trial of estrogen/

progesterone

Asherman’s

syndrome

Amenorrhea

uterus and outflow tract

Normal

Pregnancy β-hCG

FSH

Abnormal

Abnormal

Normal Normal/low

PCOS

Normal

Karyotype +

–

FIGURE 393-2 Algorithm for evaluation of amenorrhea. β-hCG, β-human chorionic gonadotropin; FSH, follicle-stimulating hormone; GYN, gynecologist; MRI, magnetic

resonance imaging; PRL, prolactin; R/O, rule out; TSH, thyroid-stimulating hormone.

3036 PART 12 Endocrinology and Metabolism

of HA generally can be made on the basis of a careful history, a physical

examination, and the demonstration of low levels of gonadotropins

and normal prolactin levels. Eating disorders, excessive exercise, and

chronic disease must be specifically excluded. An atypical history,

headache, signs of other hypothalamic dysfunction, or hyperprolactinemia, even if mild, necessitates cranial magnetic resonance imaging

(MRI) to exclude a neuroanatomic cause. Up to 10% of women with

HA may have some features of PCOS (irregular menses, increased

ovarian volume with polycystic appearing ovaries, higher anti-müllerian

hormone [AMH] levels, and slightly elevated androgen levels).

HYPERGONADOTROPIC HYPOGONADISM Ovarian failure is considered premature when it occurs in women <40 years old and accounts

for ~10% of secondary amenorrhea. Primary ovarian insufficiency

(POI) has replaced the terms premature menopause and premature

ovarian failure in recognition of the continuum of impaired ovarian

function encompassed by this disorder. Ovarian insufficiency is associated with the loss of negative feedback restraint on the hypothalamus

and pituitary, resulting in increased FSH and LH levels. FSH is a better

marker of ovarian failure because of loss of negative feedback effects of

both estradiol and the inhibins and because its levels are less variable

than those of LH. AMH levels will also be low in patients with POI but

are more frequently used in management of infertility. As with natural

menopause, POI may wax and wane, and serial measurements may

be necessary to establish the diagnosis. The presentation may include

irregular menses or complete cessation of menses, hot flashes, and

vaginal dryness.

Once the diagnosis of POI has been established, further evaluation

is indicated because of other health problems that may be associated

with POI. Although POI is most commonly of unknown cause, it also

occurs in association with a variety of chromosomal abnormalities

(most often Turner’s syndrome), autoimmune polyglandular failure

syndromes, and other rare disorders. Radiotherapy and chemotherapy

may reduce ovarian reserve, with effects on both the oocytes and the

supporting granulosa cells. New approaches, including ovarian, oocyte,

and embryo cryopreservation, should be offered to women of reproductive age prior to gonadotoxic chemotherapy or pelvic radiation

treatment. The recognition that early ovarian insufficiency occurs in

premutation carriers of the fragile X syndrome is important because of

the increased risk of severe intellectual disability in male children with

FMR1 mutations. Thus, follow-up testing should include a karyotype

in all POI patients, serum anti-cortical and 21-hydroxylase antibodies

(specific but not sensitive for subsequent adrenal insufficiency), thyroid function and thyroid peroxidase antibodies, FMR1 premutation

screening, and assessment of bone mineral density. Ovarian biopsy

is not indicated. Although the number of genetic causes of POI is

increasing, routine testing for mutations other than FMR1 is currently

not recommended.

Hypergonadotropic hypogonadism occurs rarely in other disorders,

such as mutations in the FSH or LH receptors. Aromatase deficiency

and 17α-hydroxylase deficiency are associated with decreased estrogen

and elevated gonadotropins and with hyperandrogenism and hypertension, respectively. Gonadotropin-secreting tumors in women of

reproductive age generally present with high, rather than low, estrogen

levels and cause ovarian hyperstimulation or dysfunctional bleeding.

TREATMENT

Hypo- and Hypergonadotropic Causes of Amenorrhea

Amenorrhea almost always is associated with chronically low levels

of estrogen, whether it is caused by hypogonadotropic hypogonadism or ovarian insufficiency. Development of secondary sexual

characteristics requires gradual titration of estradiol replacement

with eventual addition of progestin. Hormone replacement with

either low-dose estrogen/progesterone regimens or oral contraceptive pills is recommended until the usual age of menopause

for bone and cardiovascular protection. In women with functional

HA or anorexia nervosa, hormone replacement alone may not

be sufficient to restore or maintain bone density. Patients with

hypogonadotropic hypogonadism who are interested in fertility

require treatment with both exogenous FSH and LH. Patients with

POI can consider oocyte donation, which has a high rate of success

in this population, although its use in women with Turner’s syndrome is limited by significant cardiovascular risk in pregnancy.

POLYCYSTIC OVARIAN SYNDROME The diagnosis of PCOS is made

in adult women using the Rotterdam criteria: irregular menses (<8

menses per year), clinical or biochemical hyperandrogenism (elevated

total or free testosterone, modified Ferriman-Gallwey score >4–6

depending on ethnicity, see Chap. 394), and polycystic-appearing ovaries on ultrasound (≥20 antral follicles or ovarian volume ≥10 cm3

 in at

least one ovary). The presence of two of the three criteria will confirm

the diagnosis, resulting in different phenotypes, namely, hyperandrogenic or non-hyperandrogenic. PCOS is a diagnosis of exclusion, and

other etiologies for irregular menses and hyperandrogenism should

be excluded (hypothyroidism, hyperprolactinemia, adrenal sources

for hyperandrogenism). Diagnosis in adolescents maybe difficult to

establish, and it is recommended to wait at least 3 years after menarche

before confirming the diagnosis. In adolescents, the diagnosis is based

on irregular menses and hyperandrogenism criteria only, as the ultrasound criteria are not established for this age group. The prevalence of

obesity is high in PCOS and significantly increases the risk of comorbidities including metabolic syndrome, type 2 diabetes, dyslipidemia,

and hypertension. The failure of regular ovulation results in irregular

menses and increased risk of endometrial hyperplasia and endometrial cancer (two- to sixfold increased risk). Abnormalities in GnRH

pulsatility result in elevated LH and increased production of ovarian

androgens. Insulin resistance associated with PCOS may also contribute to increased insulin-stimulated ovarian androgen production. An

alternate source of androgens, namely 11-oxygenated androgens, has

also been shown to be elevated in women with PCOS. Genome-wide

association studies in diverse populations and PCOS phenotypes have

identified several loci associated with PCOS. Symptoms generally

begin in adolescence and are modified by obesity and age, such that

by the fourth decade of life, most women with PCOS will have regular

menses and normal serum androgens. Lean oligo-ovulatory patients

with PCOS generally have high LH levels in the presence of normal

to low levels of FSH and estradiol, although given the pulsatility of

LH secretion, a random serum LH/FSH ratio is not included in the

diagnostic criteria.

TREATMENT

Polycystic Ovarian Syndrome

The first-line treatment of women with PCOS not attempting pregnancy is combined hormonal contraceptives to regulate menstrual

cycles and decrease serum androgens by increasing sex hormone–

binding globulin levels. Although serum androgens decrease by

3 months after initiating hormonal therapy, it may take longer to

observe the beneficial effects on hirsutism and acne. Patients should

be evaluated for metabolic comorbidities and given hormonal contraceptives containing the lowest effective dose of estrogen, either

in a cyclic or continuous manner. If there is an inadequate response

to hormonal contraceptives for management of hyperandrogenic

symptoms, antiandrogens, such as spironolactone and flutamide,

can be considered (Chap. 394). Endometrial protection can also be

achieved with the use of progestins (medroxyprogesterone acetate,

5–10 mg, or Prometrium [progesterone], 200 mg daily for 10–14 days

at least every 3 months, or a levonorgestrel intrauterine device

[IUD]). All women with PCOS should be screened for obesity,

hypertension, and glycemic control at the time of diagnosis and

then at regular intervals. Overweight and obese women should

also have a fasting lipid profile at the time of diagnosis. Lifestyle

management should be recommended in all women with PCOS,

and metformin should be considered for managing cardiometabolic

risk factors (Chap. 408). Women with PCOS are at an increased risk

of gestational diabetes, gestational hypertension, and preeclampsia.

3037 Menstrual Disorders and Pelvic Pain CHAPTER 393

TABLE 393-1 Gynecologic Causes of Pelvic Pain

ACUTE CHRONIC

Cyclic pelvic pain Mittelschmerz

Dysmenorrhea

Noncyclic pelvic

pain

Pelvic inflammatory

disease

Ruptured or hemorrhagic

ovarian cyst, endometrioma,

or ovarian torsion

Ectopic pregnancy

Endometritis

Acute growth or

degeneration of uterine

myoma

Threatened abortion

Endometriosis

Fibroids

Adenomyosis

Adhesions and retroversion of

the uterus

Pelvic malignancy

Vulvodynia

Chronic pelvic inflammatory

disease

Tuberculous salpingitis

History of sexual abuse

Pelvic congestion syndrome

Lifestyle management is the first-line treatment prior to attempting

pregnancy (Chap. 396). Letrozole, an aromatase inhibitor, and

clomiphene citrate, a selective estrogen response modulator, are

effective first-line treatments for ovulation induction. Exogenous

gonadotropins can be used by experienced practitioners; a diagnosis

of polycystic ovaries increases the risk of hyperstimulation, even in

women with regular, ovulatory menstrual cycles. Metformin is frequently used in patients with PCOS and is appropriate as an adjunct

with diet and exercise for obese women with PCOS or for treatment

of diabetes or impaired glucose tolerance, as in non-PCOS patients.

However, metformin alone is not recommended for endometrial

protection or treatment of hyperandrogenic symptoms, infertility,

pregnancy loss, or prevention of gestational diabetes.

■ PELVIC PAIN

The mechanisms that cause pelvic pain are similar to those that cause

abdominal pain (Chap. 15) and include inflammation of the parietal

peritoneum, obstruction of hollow viscera, vascular disturbances, and

pain originating in the abdominal wall. Pelvic pain may reflect pelvic

disease per se but also may reflect extrapelvic disorders that refer pain

to the pelvis. In up to 60% of cases, pelvic pain can be attributed to gastrointestinal problems, including appendicitis, cholecystitis, infections,

intestinal obstruction, diverticulitis, and inflammatory bowel disease.

Urinary tract and musculoskeletal disorders are also common causes

of pelvic pain.

APPROACH TO THE PATIENT

Pelvic Pain

As with all types of abdominal pain, the first priority is to identify life-threatening conditions (shock, peritoneal signs) that may

require emergent surgical management. The possibility of pregnancy should be identified as soon as possible by menstrual history

and β-human chorionic gonadotropin (β-hCG) testing. A thorough

history that includes the type, location, radiation, and recurrence

can help identify the cause of acute pelvic pain. Specific associations

with vaginal bleeding, sexual activity, defecation, urination, movement, or eating should be specifically sought. Determination of

whether the pain is acute versus chronic and cyclic versus noncyclic

will direct further investigation (Table 393-1). However, disorders

that cause cyclic pain occasionally may cause noncyclic pain, and

the converse is also true.

■ ACUTE PELVIC PAIN

Pelvic inflammatory disease (PID) refers to infection of the upper genital tract and may present with a spectrum of symptoms. In the acute

setting, the most common presentation is bilateral lower abdominal

pain of recent onset that may be exacerbated with sexual activity. Risk

factors for PID include history of multiple sexual partners, prior sexually transmitted infections (STIs), history of recent uterine procedures,

and age <25 years. However, any sexually active woman can be at risk

for PID. PID associated with tubo-ovarian abscess or peritonitis may

present with severe pain, fever, and peritoneal signs. Abnormal uterine

bleeding may occur in about one-third of patients. Cervical motion tenderness, uterine and adnexal pain, and vaginal discharge are common

findings on pelvic examination. The presence of right upper quadrant

pain is suggestive of perihepatitis (Fitz-Hugh–Curtis syndrome).

The diagnosis of PID is established based on symptoms and clinical

examination and can be aided by a wet mount preparation of vaginal

discharge and nucleic acid amplification tests for Chlamydia trachomatis

and Neisseria gonorrhoeae. Of note, a presumptive clinical diagnosis is

sufficient to prescribe treatment even in the absence of positive test

results, as PID can occur due to other vaginal and enteric pathogens.

Pelvic imaging can be obtained based on symptoms, findings of the

pelvic examination, or if there is lack of response to therapy. With

public health efforts to control STIs, the incidence and severity of PID

have declined in the United States and Europe; however, this is not the

case in the developing world. Subclinical PID with its attendant risks of

infertility and ectopic pregnancy remains a significant problem worldwide. Public health and professional organizations recommend annual

testing for C. trachomatis in all sexually active women <25 years old

and both C. trachomatis and N. gonorrhoeae in all women at increased

risk. Adnexal pathology can present acutely and may be due to rupture,

bleeding, or torsion of ovarian cysts or, much less commonly, the fallopian tubes. Rupture of an ovarian cyst may be diagnosed based on the

acute presentation in a reproductive-age woman and pelvic ultrasound

findings of a simple, collapsed or hemorrhagic cyst, with or without

free fluid in the pelvis. Ovarian torsion typically presents as acute

onset of unilateral, intermittent pain and is a diagnosis of exclusion

unless absent blood flow to the ovary is demonstrated via Doppler

ultrasound imaging. Neoplasms of the ovary or fallopian tube are much

less common causes of acute pain. Ectopic pregnancy represents 2% of

all pregnancies and most commonly occurs in the fallopian tubes. It

may present with acute lower abdominal pain, hemodynamic instability, and peritoneal signs. The index of suspicion should be high in any

reproductive-age woman presenting with abdominal pain or vaginal

bleeding irrespective of current use of contraception. Risk factors for

an ectopic pregnancy include history of tubal disease, pelvic infection,

tubal surgery, previous ectopic pregnancy, infertility, smoking, and current use of IUD, although a large proportion may have no risk factors.

Rupture of the fallopian tube remains a life-threatening emergency; the

incidence depends on access to care but is ~18% in developed countries. Diagnosis of an ectopic pregnancy can be established by assessing the patient’s menstrual history and symptoms, measuring β-hCG

levels, and performing pelvic ultrasound imaging. The discriminatory

zone refers to β-hCG values above which the landmarks of a normal

intrauterine pregnancy should be seen on ultrasound. Absence of an

intrauterine pregnancy and presence of an adnexal mass or free fluid

increase the likelihood of an ectopic pregnancy. Threatened abortion

may also present with amenorrhea, abdominal pain, and vaginal bleeding in the setting of an intrauterine pregnancy with cardiac activity in

the first trimester of pregnancy. Although more common than ectopic

pregnancy, it is rarely associated with systemic signs. Uterine pathology

includes endometritis and, less frequently, degenerating leiomyomas

(fibroids) present with acute pain. Endometritis often is associated with

vaginal bleeding and systemic signs of infection. It occurs in the setting

of STIs, uterine instrumentation, or postpartum infection.

TREATMENT

Acute Pelvic Pain

Treatment of acute pelvic pain depends on the suspected etiology

but may require surgical or gynecologic intervention. Immediate

treatment of PID is indicated upon diagnosis, even if the diagnosis

is presumed or the symptoms are mild, due to long-term complications resulting in increased risk of ectopic pregnancy and infertility. Treatment in patents eligible for outpatient management

3038 PART 12 Endocrinology and Metabolism

includes 250 mg IM ceftriaxone and a 14-day course of oral

doxycycline 100 mg twice daily. If the presentation is acute

with high fever, nausea, vomiting, severe abdominal pain, or

presence of tubo-ovarian abscess, inpatient therapy is recommended (Chap. 136). Conservative management is an important

consideration for ovarian cysts, if torsion is not suspected, to avoid

unnecessary surgery and associated risks of reduced fertility due to

cystectomy or adhesions. If surgery is performed, it is preferable

to perform a cystectomy, removing the cyst wall and leaving the

remaining ovary, in a reproductive-age woman. Combined hormonal contraceptives are recommended in women with a history

of recurrent ovarian cyst formation. Surgical treatment may be

required for ectopic pregnancies when the patient presents with

acute pain, is hemodynamically unstable, or has signs of intraperitoneal bleeding. The choice of salpingectomy versus salpingostomy

is based on patient’s presentation, desire for future child bearing,

and prior pelvic infections. Clinically stable women presenting with

unruptured ectopic pregnancies may be appropriate for treatment

with methotrexate, which is effective in ~90% of cases when multiple doses are used. Threatened abortion is managed conservatively

even in the presence of a subchorionic hemorrhage. The treatment

of endometritis is similar to PID. Pain from a degenerating fibroid,

if visualized on pelvic sonography, can be managed with nonsteroidal

anti-inflammatory drugs (NSAIDs).

CHRONIC PELVIC PAIN

Chronic pelvic pain is a complex condition resulting from gynecologic,

urologic, or gastrointestinal organs and contributes to significant frustration and burden of disease. Common gynecologic conditions contributing to chronic pain are endometriosis, fibroids, adenomyosis, and

adnexal pathology. Estimated prevalence rates range from 5 to 20% for

cyclic and noncyclic pain. In addition to a detailed history and physical

exam, the evaluation of chronic pelvic pain typically includes a pelvic

ultrasound. As causes other than those related to the female reproductive system are common, referral should be made to other specialists,

as appropriate. Neuromuscular and psychosomatic etiologies should

also be considered.

Some women experience discomfort at the time of ovulation (mittelschmerz or ovulation pain). The pain can be quite intense but is

generally of short duration. The mechanism is thought to involve rapid

expansion of the dominant follicle, although it also may be caused by

peritoneal irritation by follicular fluid released at the time of ovulation.

Dysmenorrhea typically refers to the crampy lower abdominal midline discomfort that begins with the onset of menstrual bleeding and

gradually decreases over 12–72 h. It may be associated with nausea,

diarrhea, fatigue, and headache and occurs in 60–93% of adolescents,

beginning with the establishment of regular ovulatory cycles. Its

prevalence decreases after pregnancy and with the use of oral contraceptives. Primary dysmenorrhea results, in a majority of cases, from

hormone-dependent prostaglandin (PG) pathway mechanisms that

cause intense uterine contractions, decreased blood flow, and increased

peripheral nerve hypersensitivity, resulting in pain. However, variability

in response to cyclooxygenase inhibitors suggests that PG-independent

pathways, such as platelet activating factor, may also mediate inflammation. Secondary dysmenorrhea is caused by underlying pelvic pathology.

Endometriosis results from the presence of endometrial glands and

stroma outside the uterus. These deposits of ectopic endometrium

respond to hormonal stimulation and are associated with dysmenorrhea, painful intercourse, painful bowel movements, and tender

nodules that may be palpated along the uterosacral ligaments during

pelvic exam. The stage/severity of endometriosis does not always correlate with the extent of pain, and pain associated with endometriosis

can be cyclic or continuous. Transvaginal pelvic ultrasound is part of

the initial workup and may detect an endometrioma within the ovary

or, in severe cases, rectovaginal or bladder nodules. The CA125 level

may be increased, but it has low negative predictive value. Diagnostic

laparoscopy is performed when patients do not respond to empiric

treatment. If endometriosis is detected, the severity can be staged and

the endometriotic lesions ablated or excised. The prevalence is lower in

black and Hispanic women than in Caucasians and Asians.

Large fibroids can cause chronic pelvic pain or pressure, and submucosal fibroids may be associated with dysmenorrhea. Other secondary

causes of dysmenorrhea include adenomyosis, a condition caused

by the presence of ectopic endometrial glands and stroma within the

myometrium. Chronic PID maybe associated with ongoing pelvic pain

and is associated with tuberculosis or actinomycosis. Pelvic congestion

syndrome is associated with pelvic varicosities with low blood flow, resulting in pelvic venous congestion. However, this is no clear evidence to

indicate that this finding is associated with chronic pelvic pain.

TREATMENT

Chronic Pelvic Pain

DYSMENORRHEA

Local application of heat is of some benefit. Exercise, sexual activity, a vegetarian diet, use of vitamins D, B1

, B6

, and E and fish oil,

acupuncture, and yoga have all been suggested to be of benefit, but

studies are not adequate to provide recommendations. However,

NSAIDs are very effective and provide >80% sustained response

rates. Ibuprofen, naproxen, ketoprofen, mefanamic acid, and nimesulide are all superior to placebo. For best response, treatment

should be initiated prior to the onset of menses and continued for

at least 2–3 days. Combined oral contraceptives taken cyclically or

continuously effectively reduce symptoms of dysmenorrhea.

ENDOMETRIOSIS

Combined hormonal contraceptives or continuous progestin

(either orally or a levonorgestrel IUD) are used for the treatment

of endometriosis. Evidence of an endometrioma on ultrasound

imaging can be medically managed and does not require surgical

removal unless symptomatic. Patients who do not respond to

medical management and laparoscopic resection of endometriotic

lesions can be offered GnRH agonist suppression with add-back

therapy or aromatase inhibitors.

Chronic pain and dysmenorrhea associated with fibroids can

be managed surgically depending on the number and location of

fibroids and associated symptoms. Chronic pain and dysmenorrhea

associated with adenomyosis can be managed with combined hormonal treatment, levonorgestrel IUD, or hysterectomy after child

bearing is complete.

■ FURTHER READING

Bloomfield H et al: Screening pelvic examinations in asymptomatic

average risk adult women. WA-ESP Project #09-009; 2013.

Bouilly J et al: Identification of multiple gene mutations accounts for

the new genetic architecture of ovarian insufficiency. J Clin Endocrinol Metab 101:4541, 2016.

Brunham RC et al: Pelvic inflammatory disease. N Engl J Med

372:2039, 2015.

Fourman LR, Fazeli PK: Neuroendocrine causes of amenorrhea—An

update. J Clin Endocrinol Metab 100:812, 2015.

Ju H et al: The prevalence and risk factors of dysmenorrhea. Epidem

Rev 36:104, 2014.

Morley LC et al: On behalf of the Royal College of Obstetricians and

Gynecologists. Metformin therapy for the management of infertility

in women with polycystic ovary syndrome. Scientific Impact Paper

No. 13. BJOG 124:e306, 2017.

Oladosu FA et al: Nonsteroidal anti-inflammatory drug resistance in

dysmenorrhea: Epidemiology, causes, and treatment. Am J Obstet

Gynecol 218:390, 2018.

Teede HJ et al: Recommendations from the international evidencebased guideline for the assessment and management of polycystic

ovary syndrome. International PCOS Network. Fertil Steril 110:364,

2018.

Vercellini P et al: Endometriosis: Pathogenesis and treatment. Nat

Rev Endocrinol 10:261, 2014.

3039Hirsutism CHAPTER 394

■ DEFINING HIRSUTISM

Body hair can be categorized as either vellus (fine, soft, and not pigmented) or terminal (long, coarse, and pigmented). Approximately 10%

of reproductive age women have hirsutism, defined by the presence of

excessive terminal hair growth. Hirsutism is most often idiopathic or

the consequence of androgen excess associated with polycystic ovary

syndrome (PCOS). Less frequently, it results from adrenal androgen

overproduction as occurs in nonclassic congenital adrenal hyperplasia

(CAH) (Table 394-1). Androgenization or virilization refers to a condition in which androgen levels are sufficiently high to cause deepening

of the voice, breast atrophy, increased muscle bulk, clitoromegaly, and

increased libido. Androgenization may be caused by benign hyperplasia of ovarian theca and stroma cells (e.g., hyperthecosis); it may also

be a harbinger of a serious underlying condition, such as an ovarian

or adrenal neoplasm. Cutaneous manifestations commonly associated

with hirsutism include acne and hair thinning or pattern hair loss

(androgenic alopecia).

■ HAIR FOLLICLE GROWTH AND

DIFFERENTIATION

The number of hair follicles remains unchanged over the life span, but

follicle size and the type of hair can change in response to numerous

394 Hirsutism

David A. Ehrmann

factors, particularly androgens. Androgens are necessary for terminal

hair and sebaceous gland development and mediate differentiation

of pilosebaceous units (PSUs) into a terminal hair follicle and/or a

sebaceous gland. In the former case, androgens transform the vellus

hair into a terminal hair; in the latter case, the sebaceous component

proliferates and the hair remains vellus.

There are three phases in the cycle of hair growth: (1) anagen

(growth phase), (2) catagen (involution phase), and (3) telogen (rest

phase). Depending on the body site, hormonal regulation may play an

important role in the hair growth cycle. Hair growth on the face, chest,

upper abdomen, and back typically requires elevated androgen concentrations. However, there is only a modest correlation between androgen

levels and the quantity of hair growth. This is due to the fact that hair

growth from the follicle also depends on local growth factors, and the

variability in end-organ (PSU) sensitivity to androgens. Genetic factors

and ethnic background also influence hair growth. Androgen excess

in women may result in hair thinning or loss because androgens cause

scalp hairs to spend less time in the anagen phase.

In general, dark-haired individuals tend to be more hirsute than

blond or fair individuals. Asians and Native Americans have relatively

sparse hair in regions sensitive to high androgen levels, whereas people

of Mediterranean descent are more hirsute.

■ CLINICAL ASSESSMENT

Historic elements relevant to the assessment of hirsutism include the

age at onset and rate of progression of hair growth and associated

symptoms or signs (e.g., menstrual irregularity and acne). Depending on the cause, excess hair growth typically is first noted during

the second and third decades of life. The growth is usually slow but

progressive. Sudden development and rapid progression of hirsutism

suggest the possibility of an androgen-secreting neoplasm, in which

case androgenization may also be present.

The age at onset of menstrual cycles (menarche) and the pattern

of the menstrual cycle should be ascertained; oligomenorrhea (<8

cycles per calendar year) from the time of menarche onward is more

likely to result from ovarian than adrenal androgen excess. Associated symptoms such as galactorrhea should prompt evaluation

for hyperprolactinemia (Chap. 380) or possibly hypothyroidism

(Chap. 382). Hypertension, striae, easy bruising, and centripetal

weight gain suggest hypercortisolism (Cushing’s syndrome; Chap. 386).

Rarely, patients with acromegaly present with hirsutism. Medications

such as phenytoin, minoxidil, and cyclosporine may be associated

with androgen-independent excess hair growth (i.e., hypertrichosis).

A family history of infertility and/or hirsutism may indicate inherited

disorders such as nonclassic CAH (Chap. 386).

Physical examination should include measurement of height and

weight and calculation of body mass index (BMI). A BMI >25 kg/m2

 is

indicative of excess weight for height, and values >30 kg/m2

 are often

seen in association with hirsutism, probably the result of increased

conversion of androgen precursors to testosterone. Notation should

be made of blood pressure, as adrenal causes may be associated with

hypertension. Cutaneous signs sometimes associated with androgen

excess and insulin resistance include acanthosis nigricans and skin tags.

An objective clinical assessment of hair distribution and quantity

is central to the evaluation in any woman presenting with concerns

about excessive hair growth. This assessment permits the distinction

between hirsutism and hypertrichosis and provides a baseline reference

point to gauge the response to treatment. A simple and commonly used

method to grade hair growth is the modified scale of Ferriman and

Gallwey (Fig. 394-1), in which each of nine androgen-sensitive sites

is graded from 0 (no hair growth) to 4 (hair growth typically seen in

adult men). Although it is normal for most women to have some hair

growth in androgen-sensitive sites, ~95% of non-hispanic white and

African-American women have a score <8 on this scale. Scores >8 suggest excess androgen-mediated hair growth, a finding that should be

assessed further by means of hormonal evaluation (see below). Asian

and Native American women are less likely to manifest hirsutism, and

the only cutaneous evidence of androgen excess may be pustular acne

and thinning scalp hair.

TABLE 394-1 Causes of Hirsutism

Gonadal hyperandrogenism

Ovarian hyperandrogenism

Polycystic ovary syndrome/functional ovarian hyperandrogenism

Ovarian steroidogenic blocks

Syndromes of extreme insulin resistance

Ovarian neoplasms

Hyperthecosis

Adrenal hyperandrogenism

Premature adrenarche

Functional adrenal hyperandrogenism

Congenital adrenal hyperplasia (nonclassic and classic)

Abnormal cortisol action/metabolism

Adrenal neoplasms

Other endocrine disorders

Cushing’s syndrome

Hyperprolactinemia

Acromegaly

Peripheral androgen overproduction

Obesity

Idiopathic

Pregnancy-related hyperandrogenism

Hyperreactio luteinalis

Thecoma of pregnancy

Drugs

Androgens

Oral contraceptives containing androgenic progestins

Minoxidil

Phenytoin

Diazoxide

Cyclosporine

Valproic Acid

Ovotesticular disorders of sex development

3040 PART 12 Endocrinology and Metabolism

■ HORMONAL EVALUATION

Androgens are secreted by the ovaries and adrenal glands in response

to their respective tropic hormones: luteinizing hormone (LH) and

adrenocorticotropic hormone (ACTH). Testosterone is the principal

circulating steroid involved in the etiology of hirsutism; other steroids that may contribute to the development of hirsutism include

androstenedione and dehydroepiandrosterone (DHEA) and its sulfated

form (DHEAS). The ovaries and adrenal glands normally contribute

about equally to testosterone production. Approximately half of the

total testosterone originates from direct glandular secretion, and the

remainder is derived from the peripheral conversion of androstenedione and DHEA (Chap. 381).

1

1

1

1

1

1

1 2 3

1

1

Upper lip

Chin

Chest

Abdomen

Pelvis

Upper back

Lower back

Upper arms

2

2

2

2

2

2

2

2

3

3

3

3

3

3 4

3

3

4

4

4

4

4

4

4

4

Thighs

FIGURE 394-1 Hirsutism scoring scale of Ferriman and Gallwey. The nine body areas that have androgen-sensitive areas are graded from 0 (no terminal hair) to 4 (frankly

virile) to obtain a total score. A normal hirsutism score is <8. (Modified with permission from LJ DeGroot, JL Jameson: Endocrinology, 5th ed. Philadelphia, PA: Saunders;

2006.)

3041Hirsutism CHAPTER 394

Testosterone is the most important circulating androgen, but it is a

precursor hormone in mediating hirsutism. Testosterone is converted

to dihydrotestosterone (DHT) by the enzyme 5α-reductase, which is

located in the PSU. DHT is more potent than testosterone as it has a

higher affinity for, and slower dissociation from, the androgen receptor.

The local production of DHT allows it to serve as the primary mediator

of androgen action at the level of the PSU. There are two isoenzymes of

5α-reductase: type 2 is found in the prostate gland and in hair follicles,

and type 1 is found primarily in sebaceous glands.

One approach to the evaluation and treatment of hirsutism is

depicted in Fig. 394-2. In addition to measuring blood levels of testosterone and DHEAS, it is often important to measure the level of free

(or unbound) testosterone, i.e., the fraction of testosterone that is not

bound to its carrier protein, sex hormone–binding globulin (SHBG).

Unbound testosterone is biologically available for conversion to DHT

and binding to androgen receptors. Both hyperinsulinemia and androgen excess decrease hepatic production of SHBG, resulting in levels of

total testosterone within the high-normal range, whereas the unbound

hormone is elevated more substantially. Although there is a decline

in ovarian testosterone production after menopause, ovarian estrogen

production decreases to an even greater extent, and the concentration

of SHBG is reduced. Consequently, there is an increase in the relative

proportion of unbound testosterone, and it may exacerbate hirsutism

after menopause.

A baseline plasma total testosterone level >12 nmol/L (>3.5 ng/mL)

usually indicates an androgen-producing tumor, whereas a level

>7 nmol/L (>2 ng/mL) is suggestive of tumor but may also be observed

in women with hyperthecosis. A basal DHEAS level >18.5 μmol/L

(>7000 μg/L) suggests an adrenal tumor. Although DHEAS has been

proposed as a “marker” of predominant adrenal androgen excess, it is

not unusual to find modest elevations in DHEAS among women with

PCOS. Computed tomography (CT) or magnetic resonance imaging

(MRI) should be used to localize an adrenal mass, and ultrasound

usually suffices to identify an ovarian mass if clinical evaluation and

hormonal levels suggest these possibilities.

PCOS is the most common cause of ovarian androgen excess

(Chap. 392). An increased ratio of LH to follicle-stimulating hormone (FSH) is characteristic in carefully studied patients with PCOS.

However, because of the pulsatile nature of gonadotropin secretion, a

random measurement of LH and FSH may be misleading and is not

recommended. Transvaginal ultrasound classically shows enlarged

ovaries, increased stroma, and multiple “cysts” in women with PCOS.

These so-called cysts are, in fact, preantral and early antral follicles that

result from abnormal follicular maturation. “Cystic” ovaries also may

be found in women with hypothalamic amenorrhea (Chap. 392) and

even among women without clinical or laboratory features of PCOS.

Thus, ultrasonography is often not needed to diagnose PCOS given its

relatively low specificity and its high degree of operator dependence.

Hair growth

progresses

Evaluation and Treatment of Hirsutism

Localized terminal hair growth (e.g., chin)

Trial of dermatologic

therapy

Course stable

or improving

Hair growth

progresses

Course stable

or improving

Normal

variant

Idiopathic

hirsutism

Free testosterone

normal

Free testosterone blood level

(calculated from total testosterone

and SHBG or by LC/TMS)

Free testosterone

elevated

Re-evaluate if hirsutism progresses

Hirsutism mild

and isolated

Testosterone normal

Hirsutism moderate-severe and/or

other clinical evidence of

hyperandrogenic endocrine disorder

Hyperandrogenemia Trial of dermatologic or

oral contraceptive therapy

Total testosterone blood level

by specialty assay

Medication-related

hair growth

Discontinue

if possible

Abnormal hirsutism score or

localized terminal hair growth

plus clinical evidence of a

hyperandrogenic disorder

Testosterone elevated

Major hyperandrogenic

endocrine disorders to

consider:

• Polycystic ovary syndrome

• Nonclassic congenital

 adrenal hyperplasia

• Cushing’s syndrome

• Virilizing tumor

• Hyperprolactinemia

FIGURE 394-2 Algorithm for the evaluation and treatment of hirsutism. LC/TMS, liquid chromatography/tandem mass spectrometry; SHBG, sex hormone–binding globulin.

(Reproduced with permission from KA Martin et al: Evaluation and treatment of hirsutism in premenopausal women: An endocrine society clinical practice guideline. J Clin

Endocrinol Metab 103:1233, 2018.)

3042 PART 12 Endocrinology and Metabolism

Because adrenal androgens are readily suppressed by low doses of

glucocorticoids, the dexamethasone androgen-suppression test may

broadly distinguish ovarian from adrenal androgen overproduction.

A blood sample is obtained before and after the administration of

dexamethasone (0.5 mg orally every 6 h for 4 days). An adrenal source

is suggested by suppression of unbound testosterone into the normal

range; incomplete suppression suggests ovarian androgen excess. An

overnight 1-mg dexamethasone suppression test, with measurement

of 8:00 a.m. serum cortisol, is useful when there is clinical suspicion of

Cushing’s syndrome (Chap. 386).

Nonclassic CAH is most commonly due to 21-hydroxylase deficiency but also can be caused by autosomal recessive defects in other

steroidogenic enzymes necessary for adrenal corticosteroid synthesis

(Chap. 386). Because of the enzyme defect, the adrenal gland cannot

secrete glucocorticoids (especially cortisol) efficiently. This results

in diminished negative feedback inhibition of ACTH, leading to

compensatory adrenal hyperplasia and the accumulation of steroid

precursors that subsequently are converted to androgen. Deficiency

of 21-hydroxylase can be reliably excluded by determining a morning

17-hydroxyprogesterone level <6 nmol/L (<2 μg/L) (drawn in the

follicular phase). Alternatively, 21-hydroxylase deficiency can be diagnosed by measurement of 17-hydroxyprogesterone 1 h after the administration of 250 μg of synthetic ACTH (cosyntropin) intravenously.

TREATMENT

Hirsutism

Treatment of hirsutism may be accomplished pharmacologically

or by mechanical means of hair removal. Nonpharmacologic treatments should be considered in all patients either as the only treatment or as an adjunct to drug therapy.

Nonpharmacologic treatments include (1) bleaching, (2) depilatory (removal from the skin surface) such as shaving and chemical treatments, and (3) epilatory (removal of the hair including

the root) such as plucking, waxing, electrolysis, laser, and intense

pulsed light (IPL). Despite perceptions to the contrary, shaving does

not increase the rate or density of hair growth. Chemical depilatory

treatments may be useful for mild hirsutism that affects only limited

skin areas, although they can cause skin irritation. Wax treatment

removes hair temporarily but is uncomfortable. Electrolysis is effective for more permanent hair removal, particularly in the hands of

a skilled electrologist. Laser and IPL are used to treat large areas of

pigmented, terminal hair. Light of specific wavelength, duration,

and energy is absorbed by melanin in the hair shaft and follicle leading to photothermolysis. Properly delivered, this treatment delays

hair regrowth and causes permanent hair removal in many patients.

Pharmacologic therapy is directed at interrupting one or more of

the steps in the pathway of androgen synthesis and action: (1) suppression of adrenal and/or ovarian androgen production, (2) enhancement of androgen-binding to plasma-binding proteins, particularly

SHBG, (3) impairment of the peripheral conversion of androgen

precursors to active androgen, and (4) inhibition of androgen action

at the target tissue level. Attenuation of hair growth is typically not

evident until 4–6 months after initiation of medical treatment and, in

most cases, leads to only a modest reduction in hair growth.

Combination estrogen-progestin therapy in the form of an oral

contraceptive is usually the first-line endocrine treatment for hirsutism and acne, after cosmetic and dermatologic management.

The estrogenic component of most oral contraceptives currently in

use is either ethinyl estradiol or mestranol. The suppression of LH

leads to reduced production of ovarian androgens. The reduced

androgen levels also result in a dose-related increase in SHBG, thus

lowering the fraction of unbound plasma testosterone. Estrogens

also have a direct, dose-dependent suppressive effect on sebaceous

cell function.

The choice of a specific oral contraceptive should be predicated on the progestational component, as progestins vary in

their suppressive effect on SHBG levels and in their androgenic

potential. Ethynodiol diacetate has relatively low androgenic potential, whereas progestins such as norgestrel and levonorgestrel are

particularly androgenic, as judged from their attenuation of the

estrogen-induced increase in SHBG. Norgestimate exemplifies

the newer generation of progestins that are virtually nonandrogenic. Drospirenone, an analogue of spironolactone that has both

antimineralocorticoid and antiandrogenic activities, is commonly

used as a progestational agent in combination with ethinyl estradiol.

Oral contraceptives are contraindicated in women with a history of thromboembolic disease and women with increased risk of

breast or other estrogen-dependent cancers (Chap. 395). There is a

relative contraindication to the use of oral contraceptives in smokers and those with hypertension or a history of migraine headaches.

In most trials, estrogen-progestin therapy alone improves the extent

of acne by a maximum of 50–70%. The effect on hair growth may

not be evident for 6 months, and the maximum effect may require

9–12 months owing to the length of the hair growth cycle. Improvements in hirsutism are typically in the range of 20%, but there may

be an arrest of further progression of hair growth.

Because oral contraceptives are efficacious and have fewer side

effects, they are recommended over glucocorticoids as first-line

treatment of hirsutism in CAH. If the response to oral contraceptives is inadequate, glucocorticoids may be used. The lowest effective dose of glucocorticoid should be used (e.g., dexamethasone

[0.2–0.5 mg] or prednisone [5–10 mg]) taken at bedtime to achieve

maximal suppression by inhibiting the nocturnal surge of ACTH.

Cyproterone acetate is the prototypic antiandrogen. It acts

mainly by competitive inhibition of the binding of testosterone

and DHT to the androgen receptor. In addition, it may enhance the

metabolic clearance of testosterone by inducing hepatic enzymes.

Although not available for use in the United States, cyproterone

acetate is widely used in Canada, Mexico, and Europe. Cyproterone

(50–100 mg) is given on days 1–15, and ethinyl estradiol (50 μg)

is given on days 5–26 of the menstrual cycle. Side effects include

irregular uterine bleeding, nausea, headache, fatigue, weight gain,

and decreased libido.

Spironolactone, which usually is used as a mineralocorticoid

antagonist, is also a weak antiandrogen. It is almost as effective as cyproterone acetate when used at high enough doses

(100–200 mg daily). Patients should be monitored intermittently

for hyperkalemia or hypotension, though these side effects are

uncommon. Pregnancy should be avoided because of the risk of

feminization of a male fetus. Spironolactone can also cause menstrual irregularity. It often is used in combination with an oral

contraceptive, which suppresses ovarian androgen production and

helps prevent pregnancy.

Flutamide is a potent nonsteroidal antiandrogen that is effective

in treating hirsutism, but concerns about the induction of hepatocellular dysfunction preclude its use. Finasteride is a competitive

inhibitor of 5α-reductase type 2. Beneficial effects on hirsutism

have been reported, but the predominance of 5α-reductase type 1

in the PSU appears to account for its limited efficacy. Finasteride

would also be expected to impair sexual differentiation in a male

fetus, and it should not be used in women who may become

pregnant. Although studies of dutasteride are limited in number,

it appears that this agent may have efficacy in treating scalp hair

thinning and loss as well as hirsutism. Dutasteride differs from

finasteride as it targets 5α-reductase types 1 and 2.

Ultimately, the choice of any specific agent(s) must be tailored to

the unique needs of the patient being treated. As noted previously,

pharmacologic treatments for hirsutism should be used in conjunction with nonpharmacologic approaches. It is also helpful to review

the pattern of female hair distribution in the normal population to

dispel unrealistic expectations.

■ FURTHER READING

Azarchi S et al: Androgens in women: Hormone-modulating therapies for skin disease. J Am Acad Derm 80:1509, 2019.