Transgender men: Evaluation and management

Authors:Vin Tangpricha, MD, PhDJoshua D Safer, MD, FACPSection Editors:Peter J Snyder, MDAlvin M
Matsumoto, MDDeputy Editor:Kathryn A Martin, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Dec 2019. | This topic last updated: Aug 22, 2018.

INTRODUCTION
The terms transgender and gende

r incongruence describe a situation where an individual's gender identity differs from

external sexual anatomy at birth. Health care providers should be familiar with
commonly used terms (table 1). Gender identity-affirming care, for those who desire,
can include hormone therapy and affirming surgeries as well as other procedures
such as hair removal or speech therapy [1].

This topic will use the term transgender in the broadest sense to include any person
with incongruence between gender identity and external sexual anatomy at birth.
The evaluation and management of transgender men are discussed here. The
evaluation and management of transgender women, the primary care of the
transgender adult, and gender diversity in children and adolescents are reviewed
separately. (See "Primary care of transgender individuals" and "Gender development
and clinical presentation of gender diversity in children and adolescents" and
"Management of transgender and gender diverse children and adolescents".)

STANDARDS OF CARE
Several large medical professional organizations have issued guidelines to assist
providers in the care of transgender individuals (the World Professional Association
for Transgender Health [WPATH] [1], the Endocrine Society [2], the American
College of Obstetricians and Gynecologists [ACOG] [3]).

The Endocrine Society has released updated guidelines for the treatment of gender
dysphoria/gender incongruence [2]. The new guidelines replace the term
"transsexual" with "gender dysphoria" or "gender incongruence" and specify detailed
professional qualifications for clinicians who diagnose, assess, or treat individuals
with gender dysphoria/gender incongruence. Specifically, they now suggest that
decisions regarding social transition for prepubertal youth be made in conjunction
with a mental health or similarly experienced professional. They continue to
recommend the management and monitoring of transgender adolescents and adults
by a multidisciplinary team, as well as counseling patients about the time course of
hormone-induced physical changes and options for fertility preservation. We agree
with the updated guidelines.

OVERVIEW

The following considerations are similar for transgender men and women and are
discussed in detail in the topic on transgender women.

Epidemiology (see "Transgender women: Evaluation and management", section

on 'Epidemiology')
●

Pathophysiology (see "Transgender women: Evaluation and management",

section on 'Pathophysiology')
●

Initial presentation (see "Transgender women: Evaluation and management",

section on 'Initial presentation')
●
 Initial assessment (see "Transgender women: Evaluation and management",
section on 'Initial assessment')
●

Counseling before treatment (see "Transgender women: Evaluation and

management", section on 'Counseling before treatment')

EVALUATION AND DIAGNOSIS

Diagnostic criteria — The current criteria for gender incongruence include:

Persistent incongruence between gender identity and external sexual anatomy

at birth
●

The absence of a confounding mental disorder or other abnormality

The diagnosis of gender incongruence must be made before considering

transgender hormone and surgical therapy [4]. Such diagnosis should include
screening for confounding mental health concerns.

In addition, it is essential to identify any medical and/or psychiatric diagnoses that

may require treatment before considering hormone therapy [4,5].

Presently, most cases of transgender identity are diagnosed in adulthood, but

increasingly, children and adolescents with gender dysphoria present for diagnosis
and treatment.

The clinical presentation of gender diversity in children is reviewed separately. (See

"Gender development and clinical presentation of gender diversity in children and
adolescents", section on 'Clinical presentation'.)

Gender dysphoria — Patients also may be diagnosed with gender dysphoria, which
is defined as the discomfort arising in some individuals from the incongruence
between their gender identities and their external sexual anatomy at birth.
The diagnosis of gender dysphoria is generally done by a mental health professional;
however, other health care professionals who have the appropriate experience and
training can also diagnose gender dysphoria. Mental health providers typically use
the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) to
make a diagnosis [6]. Core components of the DSM-5 diagnosis of gender dysphoria
include longstanding discomfort with the incongruence between gender identity and
external sexual anatomy at birth along with interference with social, school, or other
areas of function [6].

HORMONAL THERAPY

Transgender men (female-to-male, FTM)

Goals — The usual aim of transgender hormone therapy is to induce physical

changes to match gender identity [7]. The treatment goal is to maintain hormone
levels in the normal physiological range for the target gender. Some individuals may
identify as nonbinary (eg, having both masculine and feminine identity attributes).
While hypogonadism carries risk to bone health and should be addressed, both male
and female hormone patterns, along with the entire continuum in between, can be
safe.

Historically, some transgender individuals self-medicated with hormones for a variety

of reasons, including fear of rejection by health care providers, delays in initiation of
hormone therapy, and the cost of undergoing treatment. Therefore, there should be
careful assessment for self-medication, both past and current [8].

In transgender men, the typical goal is to stop menses and induce virilization,
including a male pattern of sexual and facial hair, change in voice, and male physical
contours. The principal hormonal treatment is a testosterone preparation.

Criteria for starting — Criteria for starting hormone therapy include [5]:

●
 Persistent, well-documented gender dysphoria/gender incongruence
●

Capacity to make a well-informed decision

●

Relevant medical or mental health issues are well controlled

Testosterone therapy — There are many available testosterone preparations and

routes of administration including injectables, gels, and buccal tablets. We suggest
either testosterone esters (administered intramuscularly or subcutaneously) or
testosterone gels, depending upon patient preference. However, higher testosterone
levels are more easily achieved with parenteral therapy.

It is common to use 50 to 100 mg of testosterone enanthate or testosterone

cypionate weekly or 200 mg every two weeks. Route of administration can be
intramuscular or subcutaneous with similar effects. Although the subcutaneous route
is not approved in the United States by the US Food and Drug Administration (FDA),
it appears to be effective and well tolerated [9-11]. In one report of 22 patients who
had tried both the intramuscular and subcutaneous route, all preferred subcutaneous
administration [11].

With parenteral testosterone therapy, serum testosterone is typically measured

midway between injections. However, some clinicians measure serum testosterone
24 hours after injection and again just before the subsequent injection. Some
clinicians start with lower doses of testosterone because transgender men are often
smaller than average men in size. The goal remains to achieve normal male levels
and that can be done as quickly as practical.

Testosterone gel (1% or 1.6%, 2.5 to 10 g/day) may also be used [4], but virilization
might be slower if lower serum testosterone concentrations are achieved than with
testosterone injection. Some clinicians switch to gels once initial virilization is
complete. This may help to avoid supraphysiologic testosterone concentrations [12].
(See "Testosterone treatment of male hypogonadism", section on 'Is the testosterone
dose therapeutic?'.)
Masculinizing effects — There are a variety of consequences of hormonal therapy
in transgender men (table 2). Testosterone causes male-pattern hair growth and an
increase in lean body mass, muscle mass, and fat mass. It also causes growth in
midline structures like the larynx and the clitoris (which may be associated with an
increase in sexual desire).

Hair – The development of sexual hair follows the pattern observed in pubertal
boys: first the upper lip, then chin, then cheeks, etc [13,14]. The degree of hair
growth might be predicted from the pattern in male members of the same family.
The same applies to the occurrence of androgenetic alopecia, "male-pattern
baldness."
●

Voice – Deepening of the voice may occur due to oropharyngeal growth and
may be irreversible [15,16].
●

Body composition – Androgen administration leads to a reduction in

subcutaneous fat but increases in abdominal fat [17]. The increase in lean body
mass is on average 4 kg, and the increase in body weight may be greater [18].
●

Acne – Acne occurs in approximately 40 percent, similar to that observed in

hypogonadal men starting androgen treatment past the age of normal puberty
[13,14].
●

Clitoral enlargement – Clitoral enlargement occurs in all, but the degree varies.
●

Sexual desire – Most subjects will note an increase in sexual desire [19-21].
●

Breasts – Androgen administration may cause a decrease in glandular tissue

[22].
●
 Guidelines have suggested hysterectomy to avoid cancer risk from endometrial
exposure to androgen [4]. However, there is no evidence for an excess risk of
endometrial cancer in transgender men receiving androgen therapy. In one trial
of 35 transgender men receiving testosterone undecanoate 1000 mg every 12
weeks for one year, mean endometrial thickness (on pelvic ultrasound)
decreased from 9.9 to 5.7 mm [19]. In a second study, histologic analysis found
inactive, atrophic endometrium in transgender men taking long-term
testosterone therapy, similar to that seen in postmenopausal biological women
not taking estrogen therapy [23].
●

The relatively lower height and the broader hip configuration of transgender men
compared with nontransgender men does not change with testosterone
treatment.

Routine monitoring — We agree with the monitoring schedule recommended by

the Endocrine Society: Evaluate the patient every three months in the first year
corresponding to dose adjustment and then one to two times per year thereafter
(table 3).

Serum testosterone concentrations should be maintained in the physiologic range for

men; endocrine monitoring should include serum testosterone, with goals of
maintaining serum concentrations approximately 400 to 800 ng/dL (13.9 to 27.7
nmol/L). For patients on testosterone injections, trough levels should be towards the
lower end of this range, while peak levels should not exceed 1000 ng/dL (34.7
nmol/L). Individuals taking testosterone gels should have similar targets, but the
serum testosterone levels achieved tend to be at the lower end of the normal range.
Serum estradiol is monitored during the first six months of testosterone treatment or
until there has been no uterine bleeding for six months. Estradiol levels should be
<50 pg/mL (184 pmol/L) (table 3).

In addition to monitoring weight and blood pressure, lab testing should include a
hematocrit because erythrocytosis is a common consequence of testosterone
administration, reported more with testosterone ester injections. Details of
biochemical testing, bone mineral density (BMD) testing, and need for mammograms
are outlined in the table (table 3). (See 'Adverse events' below.)

Cancer screening is reviewed in detail separately. Briefly, transgender men who

have undergone mastectomy do not require mammograms [24], but breast self-exam
may still be important for appropriate surveillance. However, if mastectomy is
delayed or not performed, mammography should be performed as for females in
general. In addition, pap smears should be performed in transgender men who have
cervical tissue present (table 4). (See "Primary care of transgender individuals",
section on 'Screening/preventive care'.)

Adverse events — Androgen therapy is safe for most patients [23,25]. However,
there are some potential adverse events.

Persistent bleeding — Menses usually stop within a few months of starting

testosterone [26]. However, in some individuals, bleeding may continue. Our
approach is to increase the testosterone dose modestly. Another approach is to add
an oral progestin such as medroxyprogesterone acetate (MPA; 5 to 10 mg daily
continuously) or treatment with a gonadotropin-releasing hormone (GnRH) agonist to
stop the menstrual bleeding [4].

Metabolic — The most commonly observed consequence of androgen therapy is

erythrocytosis. We agree with the Endocrine Society and suggest that men receiving
androgen therapy be monitored to keep the hematocrit less than 50 percent (table
3). Lipid changes may necessitate intervention [25].

Heart disease — As described above, the effects of androgens on transgender men

on biochemical risk markers are somewhat mixed [27]. A meta-analysis of 16 studies
concluded that cross-sex hormone therapies increase serum triglycerides in both
transgender women and transgender men [28]. However, data about patient-
important outcomes such as atherosclerosis were limited and inconclusive. In spite
of limited data, transgender persons treated with hormones should be evaluated for
cardiovascular risk factors [4]. (See "Primary care of transgender individuals",
section on 'Cardiovascular disease' and "Overview of established risk factors for
cardiovascular disease".)

Fertility considerations — Transgender individuals who take hormone therapy may

limit fertility potential unless hormones are stopped. Individuals who undergo
transgender genital surgery that includes loss of gonads lose their reproductive
potential altogether. Thus, before starting any treatment, patients should be
encouraged to consider fertility issues.

Transgender men may consider cryopreservation of oocytes or embryos [29,30].

While these options may provide preservation of fertility, the associated costs are
high, particularly for cryopreservation of oocytes or embryos, which requires ovarian
stimulation and oocyte retrieval in addition to storage fees. (See "Overview of fertility
and reproductive hormone preservation prior to gonadotoxic therapy or surgery",
section on 'Fertility preservation' and "In vitro fertilization".)

GENDER CONFIRMATION SURGERY

Gender confirmation surgery (also referred to as gender-affirming surgery) is often

the last (and most considered) step in the treatment process. Individuals can and do
live successfully in their preferred gender role without genital surgery.

The criteria for initiating genital surgical treatment include the same criteria for
hormone therapy, but an additional criterion is added due to its increased
invasiveness [1] (see 'Criteria for starting' above):

One year of continuous hormone therapy and living in the desired gender role
is expected, unless it has been determined the hormone therapy is not medically
indicated. This criterion is not required for surgeries like chest reconstruction or
other nongenital surgeries.
Additional details for surgical procedures are available in the World Professional
Association for Transgender Health (WPATH) Standards of Care [1]. (See
'Standards of care' above.)

Prior to surgery, the clinician should continue to counsel the patient to acknowledge
the limitations of what gender confirmation surgery can achieve. In addition, the
patient should continue to work closely with the supporting medical and mental
health providers as appropriate.

The most commonly desired gender confirmation surgery for transgender men is
chest reconstruction surgery (breast reduction [31]). Note that surgeons experienced
with this surgery for men should be sought out (similar to men with gynecomastia in
general).

For some transgender men, oophorectomy, hysterectomy, and/or vaginectomy may

be considered after one to two years of androgen therapy, although practice patterns
vary [4].

Genital reconstruction procedures are best performed in the few centers with
specialized expertise. The surgeries can be less popular because of their cost and
relatively high morbidity. One option is creation of a neophallus [4,32]. In other
cases, a metaidoioplasty may be performed [32,33]. With this technique, the urethra
is lengthened using an anterior vaginal wall flap to reach the tip of the phallic glans,
and the clitoris is partially released and stretched by resection of the ventral chordae.
From the labia majora, a scrotum can be constructed in which testicular prostheses
can be implanted. This surgical intervention allows the patient to urinate standing.
Alternatively, free flaps removed from arms or legs can be used to construct a
neophallus.

Sexual function after genital reconstruction surgery — Little attention has been
given to this subject, and research has been based on self-reports. As expected for
those transgender men with a neophallus, there is a correlation between sexual
function and the quality of the neophallus [34]. While not all transgender persons are
orgasmic after a neophallus is created, many report sexual satisfaction [20,35-37].
Transgender men receiving androgens generally report an increase in sexual
interest [38]. Systematic investigation is needed to gain more insight [21].

Regrets after gender confirmation surgery — Given the irreversibility of gender

confirmation surgery and, to a lesser degree, of cross-sex hormone administration, it
would be desirable to have insight into factors that predict success or failure.
Although regrets are rare, they do occur. Regrets are seen more often in those with
difficulty in transitioning their appearance or limited social skills [35,39].

PSYCHOSOCIAL OUTCOMES OF TREATMENT

Transgender treatment that includes hormonal therapy results in significant

improvement in quality-of-life and psychosocial outcomes [40]. This was illustrated in
a meta-analysis of 28 studies that enrolled 1833 transgender individuals (1093
transgender women, 801 transgender men) who underwent transgender treatment
that included hormones [35]. In the pooled analysis, the percentage of patients
reporting improvements in symptoms included:

Gender dysphoria – 80 percent

●

Psychological symptoms – 78 percent

●

Quality of life – 80 percent

●

Sexual function – 72 percent

Management of hyperprolactinemia
Author:Peter J Snyder, MDSection Editor:David S Cooper, MDDeputy Editor:Kathryn A Martin, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Dec 2019. | This topic last updated: Oct 20, 2019.
INTRODUCTION

Lactotroph adenomas (prolactinomas) are more amenable to pharmacologic

treatment than any other kind of pituitary adenoma because of the availability of
dopamine agonists, which usually decrease both the secretion and size of these
tumors. For the minority of lactotroph adenomas that do not respond to dopamine
agonists, other treatments must be used. Hyperprolactinemia due to nonadenoma
causes should also be treated if it causes hypogonadism.

This topic will review the major issues concerning the therapy of hyperprolactinemia
due to lactotroph adenomas and other causes, with the exception of treatment during
pregnancy, which is discussed separately. The causes, clinical manifestations, and
diagnosis of hyperprolactinemia are also discussed elsewhere. (See "Management
of lactotroph adenoma (prolactinoma) during pregnancy" and "Causes of
hyperprolactinemia" and "Clinical manifestations and evaluation of
hyperprolactinemia".)

INDICATIONS FOR TREATMENT

There are two principal reasons why patients with hyperprolactinemia may need to
be treated: existing or impending neurologic symptoms due to the large size of a
lactotroph adenoma, and hypogonadism or other symptoms due to
hyperprolactinemia, such as galactorrhea [1,2].

A third indication is in women with mild hyperprolactinemia and normal cycles who
are trying to conceive as they may have subtle luteal phase dysfunction (see
"Clinical manifestations and evaluation of hyperprolactinemia", section on 'Menstrual
cycle dysfunction'). Our approach to management is similar to that suggested by the
Endocrine Society Guidelines [2].

Adenoma size — A lactotroph adenoma (prolactinoma) 1 cm or more in size is a

macroadenoma. Treatment is usually essential when the tumor is large enough to
cause neurologic symptoms, such as visual impairment or headache (see "Causes,
presentation, and evaluation of sellar masses", section on 'Clinical manifestations').
Treatment is usually desirable when the adenoma extends outside of the sella and
abuts or elevates the optic chiasm, or invades the cavernous or sphenoid sinuses or
the clivus; lesions of this size are likely to continue to grow and eventually cause
neurologic symptoms.

Microadenomas are less than 1 cm in diameter. Studies of the natural history of

microadenomas show that 95 percent do not enlarge during four to six years of
observation [3,4]. The 5 percent that do enlarge should be treated because of the
increase in size alone. (See 'Withdrawal of dopamine agonists' below.)

Prolactin secretion by lactotroph adenomas is usually proportional to their size.

Adenomas <1 cm in diameter are typically associated with serum prolactin values
below 200 ng/mL (8.7 nmol/L), those approximately 1 to 2 cm in diameter with values
between 200 and 1000 ng/mL (8.7 to 43.48 nmol/L), and those greater than 2 cm in
diameter with values above 1000 ng/mL (43.48 nmol/L) and as high as 50,000 ng/mL
(2173.91 nmol/L) (figure 1). There are exceptions to this generalization, however, as
occasional patients have a large lactotroph adenoma but only modest
hyperprolactinemia. Such adenomas are generally less well differentiated and
respond less well to dopamine agonists than the more typical adenomas.

In contrast to the extremely high serum prolactin concentrations that may be seen
with lactotroph macroadenomas, prolactin levels due to nonadenoma causes rarely
exceed 200 ng/mL (8.7 nmol/L). (See "Clinical manifestations and evaluation of
hyperprolactinemia", section on 'Serum prolactin concentrations'.)

Symptoms — Treatment of hyperprolactinemia is indicated when it causes

hypogonadism by suppressing gonadotropin secretion or when it causes bothersome
galactorrhea [1]. The clinical manifestations of hyperprolactinemia are reviewed in
detail separately. (See "Clinical manifestations and evaluation of
hyperprolactinemia".)

Premenopausal women
 ●

In premenopausal women, serum prolactin concentrations >100 ng/mL (4.35

nmol/L) are likely to be associated with amenorrhea and low estradiol levels
(which lead to eventual bone loss and osteoporosis if untreated). The symptoms
correlate with the magnitude of the hyperprolactinemia. Moderate degrees of
hyperprolactinemia (eg, serum prolactin values of 50 to 100 ng/mL [2.17 to 4.35
nmol/L]) cause either amenorrhea or oligomenorrhea, and milder degrees of
hyperprolactinemia (20 to 50 ng/mL [0.87 to 2.17 nmol/L]) may cause
oligomenorrhea or not affect menses but cause infertility due to insufficient luteal
phase progesterone secretion.
●

Hyperprolactinemia in premenopausal women can also cause galactorrhea. The

presence of galactorrhea alone does not require treatment unless the patient
finds it bothersome.

Postmenopausal women

Postmenopausal women have markedly low estradiol levels due to cessation of

ovarian function, and therefore, galactorrhea is rare. Hyperprolactinemia in
these women is clinically recognized only in the unusual situation when a
lactotroph adenoma becomes so large as to cause headaches or impair vision.

Men

In men, hypogonadism can cause decreased libido and energy and eventually
loss of sexual hair, loss of muscle mass, and osteoporosis. Hyperprolactinemia
in men may also be associated with erectile dysfunction, even when the serum
testosterone concentration is normal. The mechanism is unknown, but the
erectile dysfunction usually improves dramatically when the hyperprolactinemia
is corrected [5-7]. Gynecomastia and galactorrhea may occur, but both are rare.
OVERVIEW OF DOPAMINE AGONISTS

A dopamine agonist drug should usually be the first treatment for patients with
hyperprolactinemia of any cause, including lactotroph adenomas (prolactinomas) of
all sizes, because these drugs decrease serum prolactin concentrations and
decrease the size of most lactotroph adenomas [8,9]. Other approaches must be
considered for the minority of patients whose adenomas are resistant to dopamine
agonists or who cannot tolerate these drugs, and for those who are taking a
medication (such as an antipsychotic drug) that cannot be discontinued. (See
'Intolerant or inadequate response' below and 'Drug-induced hyperprolactinemia'
below.)

Choice of drug — For most patients with hyperprolactinemia, cabergoline is our first
choice, and bromocriptine is our second. Pergolide had been used for Parkinson
disease and hyperprolactinemia, but it was withdrawn from the market in the United
States because of concerns about valvular heart disease. Quinagolide is available in
some countries, but not the United States. (See 'Valvular heart disease' below.)

Cabergoline – We suggest cabergoline as the first choice because of its efficacy

and favorable side-effect profile [2]. It is an ergot dopamine agonist that is
administered once or twice a week and has much less tendency to cause
nausea than bromocriptine [10,11]. It may also be effective in patients resistant
to bromocriptine [12]. At the high doses used for the treatment of Parkinson
disease, cabergoline is associated with an increased risk of valvular heart
disease [13,14], but at the lower doses generally used for the treatment of
hyperprolactinemia, cabergoline does not appear to be associated with this risk.
(See 'Valvular heart disease' below and "Initial pharmacologic treatment of
Parkinson disease", section on 'Limited role of ergot dopamine agonists'.)
●

Bromocriptine – Bromocriptine is an ergot derivative that has been used for

approximately three decades for treatment of hyperprolactinemia. It should be
 given twice a day to have optimal therapeutic effect [8]. It is more likely to cause
nausea than cabergoline.
●

Pergolide – Pergolide is an ergot derivative that had been used primarily for the
treatment of Parkinson disease [15]. At the high dose used for Parkinson
disease (>3 mg/day), pergolide was associated with an increased risk of valvular
heart disease [13,14]. It was withdrawn from the United States market in 2007
[16], but it is still available in some countries. (See 'Valvular heart disease' below
and "Initial pharmacologic treatment of Parkinson disease", section on 'Limited
role of ergot dopamine agonists'.)
●

Other – Quinagolide (CV 205-502), a non-ergot dopamine agonist that is given

once or twice a day, is available in some countries but not the United States [17-
19]. The starting dose is 0.075 mg once a day, which can be increased to twice
a day and a maximum total daily dose of 0.9 mg. It is generally considered a
second-line drug if cabergoline is available, but unlike cabergoline, it is not an
ergot derivative so valvular heart disease is not a concern.

Efficacy — Dopamine agonists decrease prolactin secretion (figure 2) and reduce

the size of the lactotroph adenoma (image 1) in more than 90 percent of patients.
Both effects are mediated by the binding of the drug to cell-surface dopamine
receptors, leading to reductions in the synthesis and secretion of prolactin and in
adenoma cell size [20]. A review of 13 studies, as an example, showed that
bromocriptine reduced the serum prolactin concentration to normal in 229 of 280
women (82 percent) with hyperprolactinemia, and in 12 studies, in 66 of 92 patients
(71 percent) with lactotroph macroadenomas [8].

Cabergoline may be superior to bromocriptine in decreasing the serum prolactin

concentration [10,12]. This was illustrated in a trial of 459 women with
hyperprolactinemia and amenorrhea who had microadenomas or no obvious cause;
the patients who were randomized to cabergoline were more likely to have a
reduction of serum prolactin to normal (83 versus 52 percent in the bromocriptine
group) (figure 2) [10]. In addition, a meta-analysis of three trials and six observational
studies reported that cabergoline was more effective than bromocriptine in reducing
the risk of persistent hyperprolactinemia, amenorrhea, and galactorrhea (relative risk
[RR] 2.88, 1.85, and 3.41, respectively) [9].

Overall, the greater the decrease in serum prolactin concentration, the greater the
decrease in adenoma size, although there is considerable variation from patient to
patient. The effect on adenoma size is most apparent in patients with lactotroph
macroadenomas (image 1) [21].

The therapeutic efficacy of dopamine agonists may be blunted by the concurrent use
of drugs known to raise serum prolactin concentrations, including neuroleptic drugs,
metoclopramide, sulpiride, domperidone, methyldopa, verapamil, and cimetidine.

Quinagolide appears to have equivalent therapeutic effects to cabergoline in

reducing serum prolactin and adenoma size [18,22]. It is available in some countries,
but not the United States.

Time course of clinical response — The fall in serum prolactin typically occurs
within the first two to three weeks of therapy with a dopamine agonist (figure 2) [10];
in patients with macroadenomas, it always precedes any decrease in adenoma size
[18]. The decrease in adenoma size can, in many patients, be detected by imaging
within six weeks after initiation of treatment; in some patients, however, a decrease
is not apparent for six months (image 1) [21]. These benefits occur even in patients
who have impaired visual fields before therapy, occurring in 9 of 10 such patients in
each of two reports [23,24].

Following the decrease in serum prolactin and adenoma size in patients with
macroadenomas, visual and pituitary function often return to normal. Vision usually
begins to improve within days after the initiation of treatment [21,23]. There is
recovery of menses and fertility in women and of testosterone secretion, sperm
count, and erectile function in men [8,10,25-27]. Patients with macroadenomas who
are hypothyroid and/or hypoadrenal may also have a return of these functions to
normal [28].
Adverse effects

Typical — The principal side effects of dopamine agonist drugs are nausea, postural
hypotension, and mental fogginess. Less common side effects include nasal
stuffiness, depression, Raynaud phenomenon, alcohol intolerance, and constipation.
Nausea appears to be more common with bromocriptine than cabergoline.

Side effects are more likely to occur when treatment is initiated or the dose is
increased. They can be avoided in most patients by starting with a small dose (eg,
one-half of the lowest strength pill of bromocriptine once a day or half a pill of
cabergoline twice a week) and by giving it with food or at bedtime. A small
percentage of patients have side effects even at the lowest doses. In women,
nausea can be avoided by intravaginal administration [29].

Impulse control disorders — An adverse effect that has been recognized is the
onset or exacerbation of impulse control disorders, such as hypersexuality and
compulsive gambling, shopping, or eating. These behaviors had originally been
described in case reports. In a small, controlled study, 10 hyperprolactinemic
patients who were treated with cabergoline had a higher score on one scale of
impulsiveness than hyperprolactinemic patients not treated or 10 patients with a
normal prolactin [30]. In an uncontrolled study of 308 patients who had lactotroph
adenomas and were treated with cabergoline for at least three months, 17 percent
developed an impulse control disorder [31]. The increased risk of impulse control
disorders has also been described in up to 50 percent of patients taking dopamine
agonists for Parkinson disease (See "Initial pharmacologic treatment of Parkinson
disease", section on 'Impulse control disorders'.)

Valvular heart disease — Cabergoline and pergolide have been associated with
valvular heart disease in patients with Parkinson disease [13,14]. The association
appears to be dose dependent, and the pergolide doses used for Parkinson disease
were much higher than those used for hyperprolactinemia. In the United States,
pergolide was voluntarily withdrawn from the market in March 2007 due to this risk
[16]. (See "Initial pharmacologic treatment of Parkinson disease", section on 'Limited
role of ergot dopamine agonists'.)

In contrast to the excess risk of cardiac valvulopathy associated with high-dose

cabergoline use for Parkinson disease, most studies suggest that low-dose
cabergoline for hyperprolactinemia is not associated with excess risk [32-41]. In one
report of 50 patients with lactotroph adenoma treated with cabergoline, moderate
tricuspid regurgitation was more frequent (54 percent) than in 50 age- and gender-
matched subjects (18 percent) [34]. However, in a review of nine studies published
through 2008, the majority did not demonstrate an increased risk of valvular
regurgitation with cabergoline [32]. Most patients were using standard doses of
cabergoline for hyperprolactinemia (0.5 to 1.5 mg/week). Additional reassuring data
come from a prospective study of 40 patients with newly diagnosed
hyperprolactinemia treated with a median cumulative dose of 149 mg over five years
[42]. Patients were evaluated by transthoracic echocardiography before initiating
cabergoline and after 24 and 60 months of therapy; none of the patients developed
significant valvulopathy.

One hundred and ninety-one of patients who were reported in one of the studies
above [41] were followed for an additional median time of 34 months, during which
time they took a median additional 232 mg of cabergoline and had a transthoracic
echocardiogram at the beginning and end of the additional observation period. No
association was found between the dose of cabergoline and the prevalence of a
valvular abnormality [43].

However, new onset of valvular heart disease has been reported in a few patients
taking cabergoline. In one patient who was treated with 6 mg of cabergoline a week,
serial echocardiograms showed no valvular disease when the cumulative dose was
3272 mg, but a thickened and restricted aortic valve when the cumulative dose was
4192 mg [44].

Based upon the available data, we suggest using the lowest dose of cabergoline
necessary to lower prolactin to normal. We also suggest ordering cardiac
ultrasonography approximately every two years in patients who take larger than
typical doses of cabergoline (eg, greater than 2 mg per week). There are no
available data for cabergoline use in patients with preexisting valvular heart disease.
However, for patients with a lactotroph adenoma and mild valvular heart disease, we
feel it is reasonable to use cabergoline therapy since the doses used in this setting
have not been associated with an increased risk of valvular heart disease.

Withdrawal of therapy is discussed below. (See 'Withdrawal of dopamine agonists'

below.)

Cerebrospinal fluid rhinorrhea — Cerebrospinal fluid rhinorrhea may occur during

dopamine agonist treatment for very large lactotroph adenomas that extend inferiorly
and invade the floor of the sella [45,46]. Although uncommon, early recognition and
neurosurgical evaluation of this complication is important because of the potential
risk of bacterial meningitis.

MICROADENOMAS

Initial therapy (dopamine agonists) — Given the high rate of efficacy and low rate
of side effects with dopamine agonists, as well as the consequences of
hypogonadism, we recommend that these agents be used in patients with lactotroph
microadenomas who have any degree of hypogonadism. Decreasing the size of the
pituitary adenoma is not a treatment goal in these patients.

Cabergoline is the best initial choice in most circumstances because it is most

likely to be effective and least likely to cause side effects. Our approach is
consistent with the Endocrine Society hyperprolactinemia clinical guidelines [2].
The initial dose should be 0.25 mg twice a week or 0.5 mg once a week, if a
patient finds that more convenient.
●
 We now typically offer cabergoline to women who wish to become pregnant.
Bromocriptine might theoretically be a better first choice because there is more
evidence that it does not cause birth defects [47], However, available data
suggest that cabergoline is also safe in early pregnancy [48,49], and it has the
other advantages over bromocriptine described above. (See "Management of
lactotroph adenoma (prolactinoma) during pregnancy".)
●

If bromocriptine is used, we suggest a starting dose of 1.25 mg after dinner or at

bedtime for one week, then increase to 1.25 mg twice a day (after breakfast and
after dinner or at bedtime).

Response to therapy — After one month of therapy, the patient should be

evaluated for side effects and serum prolactin should be measured. Subsequent
treatment depends upon the response:

Prolactin normalized — If the serum prolactin concentration is normal and no side

effects have occurred, the initial dose should be continued. In this setting, gonadal
function will probably return within a few months. (See 'Long-term follow-up' below.)

Of note, in some patients, dopamine agonist therapy may result in restoration of

normal gonadal function (eg, normal menstrual cycles in women) even if serum
prolactin levels remain slightly high. In this case, the reproductive outcome
(menstrual function) can be followed rather than the absolute prolactin level to
determine treatment dose.

Similarly, when treating women with bothersome galactorrhea, the goal of therapy is
to lower the serum prolactin low enough to resolve the galactorrhea. This may not
require lowering prolactin into the normal range for the galactorrhea to remit.

Prolactin improved but not normal

If the serum prolactin concentration has not decreased to normal but no side
effects have occurred, the dose should be increased gradually to as much as
 1.5 mg of cabergoline two or three times a week or 5 mg of bromocriptine twice
a day. Whatever dose results in a normal serum prolactin value should be
continued. (See 'Prolactin normalized' above.)
●

If the cabergoline dose is increased above 2 mg per week, we suggest cardiac

ultrasonography every two years in patients to monitor for valvular heart
disease.

Intolerant or inadequate response

To initial therapy:
•
If the serum prolactin concentration does not decrease sufficiently to restore
normal gonadal function in response to bromocriptine (if it was chosen as
initial therapy) and if compliance seems good, changing to cabergoline may
be effective. The cabergoline dose should then be adjusted until the serum
prolactin concentration is normal. (See 'Prolactin normalized' above.)
Approximately 25 percent of patients are resistant to bromocriptine [10,12],
and most (80 percent) can achieve normal prolactin concentrations with
cabergoline therapy [12,50]. It is estimated that 10 percent of patients are
resistant to cabergoline [2].
•
If the patient cannot tolerate the first dopamine agonist administered
because of side effects, another can be tried. In women, nausea can be
avoided by vaginal administration [51], although other side effects cannot.
●

To all dopamine agonists:

•
Patients who do not respond to typical doses of dopamine agonists, eg, 2
mg of cabergoline a week, may respond to higher doses [50], but higher
doses may be associated with higher risk of valvular heart disease.
 •
If dopamine agonists have been unsuccessful or the patient cannot tolerate
them, transsphenoidal surgery or ovulation induction with clomiphene
citrate can be considered (for women wishing to become pregnant). For
women not pursuing pregnancy, estradiol and progesterone replacement
can be considered; men can consider testosterone therapy. (See 'Role of
transsphenoidal surgery' below and "Overview of ovulation induction" and
'Role of estradiol in women' below.)

Role of estradiol in women — Estradiol, along with a progestin, can be considered

as sole therapy for the hypogonadism resulting from hyperprolactinemia in women
who have lactotroph microadenomas but who cannot tolerate or do not respond to
dopamine agonists and do not want to become pregnant (see "Management of
spontaneous primary ovarian insufficiency (premature ovarian failure)", section on
'Estrogen therapy'). Estradiol is also a reasonable option for women who have
hypogonadism resulting from hyperprolactinemia due to other causes, including
antipsychotic agents. (See "Clinical manifestations and evaluation of
hyperprolactinemia" and 'Drug-induced hyperprolactinemia' below.)

Since estradiol treatment might pose a slight risk of increasing the size of the
adenoma, the serum prolactin concentration should be measured periodically in
these patients. Estradiol should not be used as the sole treatment for lactotroph
macroadenomas.

Estradiol and progestin can be administered separately in low doses as they would
be for the treatment of hypogonadism of any etiology, or estrogen can be
administered in the form of an oral contraceptive. (See "Combined estrogen-
progestin oral contraceptives: Patient selection, counseling, and use".)

Role of testosterone in men — For men with hyperprolactinemia causing

hypogonadism who cannot tolerate or who do not respond to dopamine agonists,
testosterone treatment can be considered for those who are not interested in fertility
and human chorionic gonadotropin (hCG) for those who are. (See "Testosterone
treatment of male hypogonadism" and "Induction of fertility in men with secondary
hypogonadism".)

Transsphenoidal surgery — Transsphenoidal surgery should be considered in

patients with microadenomas when dopamine agonist treatment has been
unsuccessful in lowering the serum prolactin concentration, symptoms or signs due
to hyperprolactinemia persist even after several months of treatment, and gonadal
steroid replacement is not an option, eg, when pregnancy is desired. The role of
surgery in patients with macroadenomas is reviewed below. (See 'Role of
transsphenoidal surgery' below.)

Long-term follow-up — Patients with microadenomas who achieve normal serum

prolactin concentrations should be treated for at least one year. Serum prolactin
measurements should be obtained at least every 12 months [1,2].

After approximately one year of treatment (if prolactin is normal), the dose can often
be decreased. If the prolactin has been normal for two or more years and no
adenoma is seen on magnetic resonance imaging (MRI), discontinuation of the drug
can be considered. (See 'Withdrawal of dopamine agonists' below.)

Dopamine agonists should be stopped in women who become pregnant. (See

"Management of lactotroph adenoma (prolactinoma) during pregnancy".)

Withdrawal of dopamine agonists — In a patient who had idiopathic

hyperprolactinemia (no pituitary mass at baseline) and whose serum prolactin
decreased to low normal in response to dopamine agonist treatment, we suggest
attempting to decrease the dose gradually, as long as the prolactin remains within
the normal range. If a patient has a normal prolactin for two years while taking a low
dose (eg, 0.25 mg twice a week) of cabergoline, we suggest a trial of discontinuation
of the drug. We suggest a similar approach for patients who had hyperprolactinemia
and a microadenoma prior to treatment in whom prolactin fell to normal and who
have not had evidence of an adenoma by MRI for at least two years. We suggest
considering this approach even if the patient had a macroadenoma prior to
treatment, as long as the serum prolactin has been normal and no adenoma has
been detectable by MRI for at least two years. This approach is consistent with that
of the Endocrine Society clinical guidelines [2].

If the drug is discontinued, prolactin should be measured after three months and
yearly thereafter. If the prolactin increases substantially (eg, to >100 ng/mL),
especially in a patient who originally had a macroadenoma, an MRI should be
performed.

We recommend not stopping the dopamine agonist if the prolactin increases above
normal while gradually decreasing the drug.

If serum prolactin increases after a withdrawal attempt, we suggest resuming

cabergoline therapy at the same dose that previously kept the prolactin normal and
decreased the adenoma size to undetectable.

Several studies have reported the consequences of discontinuation of dopamine

agonist treatment in patients who have hyperprolactinemia. Recurrence of
hyperprolactinemia and increase in adenoma size have been variable [52-57].

In one prospective study of 200 cabergoline-treated patients with hyperprolactinemia

(25 with idiopathic hyperprolactinemia, 105 with microadenomas, and 70 with
macroadenomas), therapy was withdrawn when serum prolactin concentrations were
normal and MRI showed no adenoma (or >50 percent reduction with no cavernous
sinus invasion and >5 mm distance from the optic chiasm) [52]. After two to five
years of observation, the following results were seen:

Hyperprolactinemia recurred in 24, 31, and 36 percent of patients with idiopathic

hyperprolactinemia, microadenomas, and macroadenomas, respectively (eg, a
remission rate [persistent normoprolactinemia] of 64 to 76 percent).
●

Adenoma regrowth was not seen in any patient.

●
 Hyperprolactinemia in patients with adenomas was more likely to recur if an
adenoma remnant was seen on MRI than if it was not when treatment was
stopped (78 versus 33 percent for macroadenomas, and 42 versus 26 percent
for microadenomas).

Most patients with a macroadenoma remnant had adenoma recurrence by seven

years of follow-up [58]. However, giant adenomas (>3 cm) may behave more
aggressively, as shown by case reports of rapid, substantial regrowth within weeks
of discontinuation of dopamine agonist medication [59,60].

In contrast, a number of other studies report higher rates of recurrent

hyperprolactinemia (eg, lower rates of remission) [53,56,60]. In a meta-analysis of 19
studies with a total of 743 patients, the overall rate of remission (persistent
normoprolactinemia) after withdrawal of dopamine agonist therapy was only 21
percent (32, 21, and 16 percent for idiopathic hyperprolactinemia,
microprolactinomas, and macroprolactinomas, respectively) [57]. Other findings
included:

Higher rate of remission in studies in which cabergoline was used (35 percent in
four studies) than in those in which bromocriptine was used (20 percent in 12
studies).
●

Higher rates of remission in studies with treatment duration longer than 24

months (34 percent) compared with studies with shorter treatment duration (16
percent).
●

Higher rate of remission in studies where a 50 percent tumor reduction was

achieved in all patients before stopping therapy (55 percent remission rate was
seen).

In summary, hyperprolactinemia may recur in a considerable number of patients

after stopping dopamine agonist therapy. The probability of remission is best the
longer the serum prolactin has been normal and no adenoma has been seen by
MRI, preferably for at least two years.

Menopause — After menopause, the drug can be discontinued and the serum
prolactin concentration can be allowed to rise. Imaging should be performed if the
value rises above 200 ng/mL to determine if the adenoma has increased to a
clinically important size. If so, drug therapy should be resumed.

MACROADENOMAS

Initial therapy — Treatment of patients with lactotroph macroadenomas, no matter

how large or how severe the neurologic sequelae, should also be initiated with a
dopamine agonist, starting with cabergoline [2], as described above for patients with
microadenomas. (See 'Microadenomas' above.) Patients whose macroadenomas
are largely cystic should also be treated initially with a dopamine agonist since this
treatment shrinks most of these [61].

Titration of dose and monitoring — The serum prolactin should be measured and
the cabergoline dose should be increased every one to three months, if necessary,
until the serum prolactin concentration becomes normal.

If vision was abnormal before therapy, it should be reassessed within one month,
although improvement may occur within a few days. Magnetic resonance imaging
(MRI) should be repeated in 6 to 12 months to determine if the size of the adenoma
has decreased.

In most patients with lactotroph macroadenomas:

The size of the adenoma decreases to approximately the same degree as the
serum prolactin concentration, although the relationship varies from patient to
patient.
●
 The decrease in size usually cannot be demonstrated until weeks or months
after the prolactin secretion has decreased (image 1).
●

The size of the adenoma can continue to decrease for years.

Once serum prolactin has normalized:

If the clinical picture is stable (no evidence of adenoma growth on MRI and no
symptoms such as headaches or visual symptoms), serum prolactin should be
measured in six months, and if normal, it should then be measured yearly.
●

Serum prolactin should be measured at any point if there are recurrent or new
symptoms.

Candidates for stopping therapy — If the serum prolactin concentration has been
normal for at least one year and the adenoma has decreased markedly in size, the
dose of the dopamine agonist can be decreased gradually, as long as the serum
prolactin remains normal [62]. Discontinuation can be considered in those patients
who had macroadenomas of modest size (eg, 1.0 to 1.5 cm), whose serum prolactin
concentrations have been normal for more than two years, and whose adenomas
can no longer be visualized by MRI for more than two years.

If the drug is discontinued, the prolactin concentration and the size of the adenoma
by MRI must be monitored.

Discontinuation should probably not be considered if the adenoma was initially >2
cm, if it can still be visualized by MRI during treatment, or if the prolactin has not
become normal during treatment. The agonist should not be discontinued entirely,
even after menopause, because hyperprolactinemia will probably recur and the
adenoma may increase in size [52,59,60]. (See 'Withdrawal of dopamine agonists'
above.)
Inadequate response or drug intolerance — We recommend the following
approach in patients who do not have a complete response to dopamine agonist
therapy:

If bromocriptine was tried first and the patient cannot tolerate it or the adenoma
does not respond to it, cabergoline should be tried.
●

If the patient cannot tolerate or the adenoma does not respond to agonist
therapy, transsphenoidal surgery should be performed, and if a significant
amount of adenoma tissue remains after surgery, radiation therapy should be
administered (see "Radiation therapy of pituitary adenomas", section on
'Lactotroph adenomas (prolactin-secreting adenomas)'). Surgery can also be
considered for the woman who has a giant adenoma and is contemplating
pregnancy. (See 'Role of transsphenoidal surgery' below.)

Role of transsphenoidal surgery — Transsphenoidal surgery should be

considered when:

Dopamine agonist treatment has been unsuccessful in lowering the serum

prolactin concentration or size of the adenoma, and symptoms or signs due to
hyperprolactinemia or adenoma size persist after several months of treatment at
high doses.
●

A woman has a giant lactotroph adenoma (eg, >3 cm) and wishes to become
pregnant even if the adenoma responds to a dopamine agonist. The rationale
for this approach is that if the patient becomes pregnant and discontinues the
agonist for the duration of pregnancy, the adenoma may increase to a clinically
important size before delivery.

Surgery is usually successful in substantially reducing serum prolactin

concentrations in patients with lactotroph adenomas, sometimes to normal [63-66]. It
is a safer procedure when performed by an experienced surgeon [67]. (See
"Transsphenoidal surgery for pituitary adenomas and other sellar masses", section
on 'Lactotroph adenomas'.)

Surgery, however, has the following limitations:

Not all of the adenoma tissue is excised in many patients, particularly those with
macroadenomas. (See "Transsphenoidal surgery for pituitary adenomas and
other sellar masses", section on 'Lactotroph adenomas'.)
●

The adenoma and hyperprolactinemia may recur within several years after
surgery. (See "Transsphenoidal surgery for pituitary adenomas and other sellar
masses", section on 'Lactotroph adenomas'.)

Complications are the same as may occur during and after transsphenoidal surgery
for any kind of pituitary adenoma.

Postoperative radiation therapy — Radiation is primarily used to prevent regrowth

of residual tumor in a patient with a very large macroadenoma after transsphenoidal
debulking of lactotroph adenomas that are resistant to cabergoline. It should not be
used for the primary treatment of patients with macroadenomas or at all for those
with microadenomas. While radiation therapy (single dose or multiple fraction)
appears to be effective in controlling growth of most pituitary macroadenomas, the
effect on aggressive lactotroph adenomas that do not respond to dopamine agonists
and cannot be entirely resected surgically is less well known. (See "Radiation
therapy of pituitary adenomas", section on 'Lactotroph adenomas (prolactin-secreting
adenomas)'.)

Complications of radiation include transient nausea, lassitude, loss of taste and

smell, loss of scalp hair at the radiation portals during and shortly after the treatment,
and possible damage to the optic nerve and neurologic dysfunction [1]. There is also
a 50 percent chance of loss of anterior pituitary hormone secretion during the
subsequent 10 years [68].
PREGNANCY

The management of lactotroph adenomas before, during, and after pregnancy is

reviewed in detail separately. (See "Management of lactotroph adenoma
(prolactinoma) during pregnancy".)

TREATMENT OF NONADENOMA CAUSES

Treatment of hyperprolactinemia due to an abnormality other than a lactotroph

adenoma varies depending on the cause:

Idiopathic hyperprolactinemia — In a substantial number of patients whose serum

prolactin concentration is between 20 and 100 ng/mL (100 mcg/L SI units), no cause
can be found; they are considered to have idiopathic hyperprolactinemia. Although
many of these patients may have microadenomas not visible on imaging studies, in
most of them, the serum prolactin concentrations change little during follow-up for
several years. Serum prolactin should be measured yearly. (See "Causes of
hyperprolactinemia".)

In patients with idiopathic hyperprolactinemia (no pituitary mass at baseline) whose

serum prolactin decreased to low-normal in response to dopamine agonist treatment,
we suggest attempting to decrease the dose gradually, as long as the prolactin
remains within the normal range. If a patient has a normal prolactin for two years
while taking a low dose (eg, 0.25 mg of cabergoline twice a week), we suggest a trial
of discontinuation of the drug. (See 'Withdrawal of dopamine agonists' above.)

Hypothalamic and pituitary disease — Any disease in or near the hypothalamus

or pituitary that interferes with the secretion of dopamine or its delivery to the
hypothalamus can cause hyperprolactinemia, including tumors and infiltrative
diseases of the hypothalamus, section of the hypothalamic-pituitary stalk (eg, due to
head trauma or surgery), and adenomas of the pituitary other than lactotroph
adenomas. If removal of the adenoma or mass is not possible, the
hyperprolactinemia should be treated with a dopamine agonist.

Drug-induced hyperprolactinemia — A number of drugs, especially antipsychotics

and some antihypertensives (verapamil, methyldopa), can cause hyperprolactinemia
(table 1) (see "Causes of hyperprolactinemia", section on 'Drug induced'). If the
hyperprolactinemia is asymptomatic, no treatment is necessary. If symptoms are
present and the hyperprolactinemia is due to a drug other than an antipsychotic
agent, we suggest discontinuing the drug as a trial. If discontinuation is not feasible,
options include switching to a drug with a similar action that does not cause
hyperprolactinemia, adding estradiol or testosterone for the hypogonadal symptoms
and/or low bone mass, or cautious administration of a dopamine agonist, as
described in the following section.

Antipsychotic drug use — If an antipsychotic drug is causing hyperprolactinemia

and hypogonadism but cannot be discontinued because it is essential, several
possible treatment options can be considered:

Addition of a dopamine agonist. This option should be undertaken very

cautiously in consultation with the treating psychiatrist since it might counteract
the dopamine antagonist property of the antipsychotic drug.
●

Change to an antipsychotic drug that does not raise prolactin, such as

quetiapine. This course should only be considered in conjunction with the
treating psychiatrist.
●

Addition of the antipsychotic drug aripiprazole to the existing antipsychotic drug.

This drug has both dopamine agonist and antagonist properties and dampens
hyperprolactinemia when added to other antipsychotic drugs such as
risperidone [69].
●
 Addition of estradiol and progestin to treat the estradiol deficiency and prevent
bone loss in women and testosterone to treat testosterone deficiency in men.
This approach will not treat the hyperprolactinemia.

Hypothyroidism — If hyperprolactinemia is solely the result of hypothyroidism, it will

remit as the hypothyroidism is corrected, so no other treatment is necessary. (See
"Causes of hyperprolactinemia", section on 'Hypothyroidism' and "Treatment of
primary hypothyroidism in adults".)

Macroprolactinemia — Macroprolactinemia or "big prolactin" is a benign condition

that does not require treatment, as it does not result from a pituitary adenoma or
cause hypogonadism.

Macroprolactin is an umbrella term used to describe nonbioactive prolactin isoforms,

usually composed of a prolactin monomer and an immunoglobulin G (IgG) molecule.
These isoforms are clinically nonreactive and range in size from approximately 150
to 170 kD (the most common form of native prolactin in serum is 23 kD in size).

Macroprolactinemia is sometimes misdiagnosed and treated as ordinary

hyperprolactinemia. Misdiagnosis can be avoided by asking the laboratory to pretreat
the serum with polyethylene glycol to precipitate the macroprolactin before the
immunoassay for prolactin

Treatment of polycystic ovary syndrome in adults

Authors:Robert L Barbieri, MDDavid A Ehrmann, MDSection Editor:William F Crowley, Jr, MDDeputy
Editor:Kathryn A Martin, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Dec 2019. | This topic last updated: Jul 17, 2019.

INTRODUCTION
The polycystic ovary syndrome (PCOS) is an important cause of androgen excess,
menstrual irregularity, and cardiometabolic dysfunction in women. When fully
expressed, the manifestations include irregular menstrual cycles, hirsutism, obesity,
insulin resistance, and anovulatory infertility.

The treatment of PCOS will be reviewed here. The epidemiology and pathogenesis,
diagnostic criteria, and clinical manifestations of PCOS are described in detail
separately. (See "Epidemiology, phenotype, and genetics of the polycystic ovary
syndrome in adults" and "Diagnosis of polycystic ovary syndrome in adults" and
"Clinical manifestations of polycystic ovary syndrome in adults".)

OVERVIEW OF APPROACH

Women with PCOS have multiple abnormalities that require attention, including
oligomenorrhea, hyperandrogenism, anovulatory infertility, and metabolic risk factors
such as obesity, insulin resistance, dyslipidemia, and impaired glucose tolerance.
Weight loss, which can restore ovulatory cycles and improve metabolic risk, is the
first-line intervention for most women. Our overall approach is similar to that
described by the Endocrine Society Clinical Guidelines [1] and the international
guidelines for the assessment and management of PCOS [2].

Goals — The overall goals of therapy of women with PCOS include:

Amelioration of hyperandrogenic features (hirsutism, acne, scalp hair loss)

●

Management of underlying metabolic abnormalities and reduction of risk factors

for type 2 diabetes and cardiovascular disease
●

Prevention of endometrial hyperplasia and carcinoma, which may occur as a

result of chronic anovulation
●
 Contraception for those not pursuing pregnancy, as women with oligomenorrhea
ovulate intermittently and unwanted pregnancy may occur
●

Ovulation induction for those pursuing pregnancy

Lifestyle changes — We suggest diet and exercise for weight reduction as the first
step for overweight and obese women with PCOS. Available evidence suggests that
lifestyle interventions (diet, exercise, and behavioral interventions) are more effective
than minimal treatment for weight loss and for improving insulin resistance and
hyperandrogenism [3]. In addition, there appear to be reproductive benefits as well.
(See 'Weight reduction' below and 'Weight loss' below.)

Oral contraceptives and risk assessment — Combined estrogen-progestin oral

contraceptives (COCs) are the mainstay of pharmacologic therapy for women with
PCOS for managing hyperandrogenism and menstrual dysfunction and for providing
contraception. COCs are associated with an increased risk of venous
thromboembolism (VTE) in all users but particularly in obese women. There have
been concerns that the presence of PCOS per se may represent an additional
independent risk factor for VTE, but available data do not support this concept. (See
"Clinical manifestations of polycystic ovary syndrome in adults", section on 'Venous
thromboembolism'.)

Our approach to the use of COCs in women with PCOS is the same as in women
without PCOS. Risk factors for VTE including obesity, patient age, and family history
of VTE should be assessed. We currently suggest using caution if COCs are
prescribed to obese women (body mass index [BMI] ≥30 kg/m2) over age 40 years
because these women are at particularly high risk for VTE. Other relative and
absolute contraindications to COC use are outlined in the Centers for Disease
Control and Prevention (CDC) United States Medical Eligibility Criteria for
Contraceptive Use. Alternatives to COCs include cyclic progestin therapy,
continuous progestin therapy (progestin-only pills [the "mini-pill"]), or a progestin-
releasing intrauterine device (IUD). Cyclic progestin therapy can induce regular
withdrawal uterine bleeding and reduce the risk of endometrial hyperplasia. Both
continuous progestin therapy (eg, a progestin-only pill such as norethindrone 0.35
mg/day) and the progestin-releasing IUD provide contraception and reduce the risk
of endometrial hyperplasia. (See 'Endometrial protection' below and "Combined
estrogen-progestin contraception: Side effects and health concerns", section on
'Cardiovascular effects'.)

Patient satisfaction with care — Women with PCOS commonly report long delays
in diagnosis and dissatisfaction with their care. In a cross-sectional study of 134
women with PCOS and 198 controls without PCOS who completed an online
evaluation of their health care providers, those with PCOS had less trust in their
primary care providers, perceived them as less qualified to treat PCOS-related
health concerns, and argued with them more often [4]. These observations highlight
opportunities for improving care for women with PCOS. (See "Diagnosis of polycystic
ovary syndrome in adults", section on 'Delays in diagnosis'.)

WOMEN NOT PURSUING PREGNANCY

Menstrual dysfunction

Endometrial protection — The chronic anovulation seen in PCOS is associated

with an increased risk of endometrial hyperplasia and possibly endometrial cancer.
(See "Clinical manifestations of polycystic ovary syndrome in adults", section on
'Endometrial cancer risk' and "Endometrial carcinoma: Epidemiology, risk factors,
and prevention", section on 'Chronic anovulation'.)

We suggest combined estrogen-progestin oral contraceptives (COCs) as first-line

therapy for menstrual dysfunction and endometrial protection [1,2].

COCs provide a number of benefits in women with PCOS, including:

Daily exposure to progestin, which antagonizes the endometrial proliferative

effect of estrogen
 ●

Contraception in those not pursuing pregnancy, as women with oligomenorrhea

ovulate intermittently and unwanted pregnancy may occur
●

Cutaneous benefits for hyperandrogenic manifestations (see 'Androgen excess'

below)

COCs affect insulin sensitivity, carbohydrate metabolism, and lipid metabolism; the
effects depend upon the estrogen dose and androgenicity of the progestin. However,
there is no evidence that women with PCOS are at greater risk for either metabolic
adverse effects or cardiovascular complications of COCs. (See 'Metabolic effects of
COCs in PCOS' below and "Combined estrogen-progestin contraception: Side
effects and health concerns" and "Clinical manifestations of polycystic ovary
syndrome in adults", section on 'Venous thromboembolism'.)

Absence of pregnancy should be documented before COCs are begun.

An approach to starting COCs in women with PCOS is described below (see 'Choice
of oral contraceptive' below). Risks and side effects of COCs (including unscheduled
bleeding) are similar to those for women without PCOS. Unscheduled bleeding and
an overview of estrogen-progestin COCs are reviewed in detail separately. (See
"Combined estrogen-progestin contraception: Side effects and health concerns" and
"Combined estrogen-progestin oral contraceptives: Patient selection, counseling,
and use".)

For women with PCOS who choose not to or cannot take COCs, alternative
treatments for endometrial protection are intermittent or continuous progestin
therapy, or a progestin-releasing intrauterine device (IUD) [5]. In this setting, we
recommend medroxyprogesterone acetate (5 to 10 mg) for 10 to 14 days every one
to two months. An alternative, but one that has been less well studied, is natural
micronized progesterone 200 mg (given for the same duration every one to two
months). Patients should be made aware that progestin therapy alone will not reduce
the symptoms of acne or hirsutism, nor will it provide contraception. However,
continuous progestin therapy with norethindrone 0.35 mg daily provides both
contraception and endometrial protection. This is a progestin-only contraceptive that
is also referred to as the "mini-pill." An alternative progestin option that provides both
endometrial protection and contraception are the levonorgestrel-releasing IUDs.
(See "Intrauterine contraception: Background and device types", section on
'Levonorgestrel IUD' and "Intrauterine contraception: Candidates and device
selection", section on 'Endometrial protection'.)

Metformin is a potential alternative to restore menstrual cyclicity as it restores

ovulatory menses in approximately 30 to 50 percent of women with PCOS [6,7]. Its
ability to provide endometrial protection is less well established, and we therefore
consider it to be second-line therapy [8,9]. (See "Metformin for treatment of the
polycystic ovary syndrome".)

When metformin is used, we suggest monitoring to confirm that ovulatory cycles

have been established. This can be done with luteal phase serum progesterone
measurements or transvaginal ultrasound. (See "Evaluation of the menstrual cycle
and timing of ovulation", section on 'Detection of ovulation' and "Metformin for
treatment of the polycystic ovary syndrome", section on 'Oligomenorrhea'.)

Androgen excess

Hirsutism — Our approach to the management of hirsutism is consistent with the

2018 Endocrine Society Clinical Practice Guidelines on Hirsutism, which suggest a
COC as first-line pharmacologic therapy for most women [10]. In addition, both the
Endocrine Society Clinical Practice Guidelines on the Diagnosis and Treatment of
Polycystic Ovary Syndrome and international guidelines for the assessment and
management of PCOS [2] suggest COCs as first-line therapy for hirsutism [1]. An
antiandrogen is then added after six months if the cosmetic response is suboptimal
(see "Treatment of hirsutism"). COCs and an antiandrogen may sometimes be
started simultaneously at the outset, particularly when the cutaneous manifestations
are bothersome to the patient. However, we typically postpone starting the
antiandrogen until completion of at least one month of COC. A serum or urine
pregnancy test should be obtained in women with oligomenorrhea or amenorrhea
prior to starting either the COC or spironolactone. (See "Treatment of hirsutism",
section on 'Antiandrogen therapy'.)

For women with hirsutism and contraindications to COCs, we sometimes use

spironolactone alone, but an alternative form of contraception is essential because, if
pregnancy occurs, an antiandrogen such as spironolactone could prevent
development of normal external genitalia in a male fetus. Spironolactone alone does
not regularize menstrual cycles, and in fact, it is sometimes associated with
menstrual irregularities.

Choice of oral contraceptive — We typically start with a COC containing 20 mcg of

ethinyl estradiol combined with a progestin such as norethindrone or norethindrone
acetate, progestins that have lower androgenicity, but similar VTE risk compared
with levonorgestrel-containing COCs (table 1). (See "Combined estrogen-progestin
contraception: Side effects and health concerns", section on 'Venous
thromboembolism'.)

Progestins with lower androgenicity include desogestrel, cyproterone acetate, and

drospirenone, but all have been associated with a possible higher risk of venous
thromboembolism (VTE). Norgestimate is a progestin with low androgenicity and
similar VTE risk to norethindrone and levonorgestrel. However, there are currently no
COCs containing 20 mcg of ethinyl estradiol with norgestimate.

Higher doses of ethinyl estradiol (30 to 35 mcg) are needed in some women for
optimal suppression of ovarian androgens and management of hyperandrogenic
features. Although transdermal or vaginal ring preparations are potential options,
they have not been well studied for the management of hirsutism. The risk of VTE
with the transdermal and vaginal ring preparations appear to be similar to COCs
containing levonorgestrel. (See "Hormonal contraceptive vaginal rings", section on
'Cardiovascular and thromboembolic events' and "Transdermal contraceptive patch",
section on 'Risk of venous thrombotic events'.)
Antiandrogens — After six months, if the patient is not satisfied with the clinical
response to COC monotherapy (for hyperandrogenic symptoms), we typically add
spironolactone 50 to 100 mg twice daily. (See "Treatment of hirsutism", section on
'Antiandrogen therapy'.)

Other available antiandrogens include finasteride, which inhibits 5-alpha-reductase

type 2, the enzyme that converts testosterone to dihydrotestosterone (DHT), and
dutasteride, an inhibitor of both 5-alpha-reductase types 1 and 2. No clinical trial data
are available for dutasteride use in hirsute women. These drugs should never be
used in women who are not using reliable contraception, as there is a substantial risk
of preventing the development of normal male external genitalia during early
pregnancy. (See "Treatment of hirsutism", section on 'Antiandrogen therapy'.)

Cyproterone acetate is an antiandrogen that is available in most countries, but not

the United States. Flutamide is also effective, but we recommend not using it
because of its potential hepatotoxicity. (See "Combined estrogen-progestin oral
contraceptives: Patient selection, counseling, and use" and "Treatment of hirsutism",
section on 'Antiandrogen therapy'.)

Other — Gonadotropin-releasing hormone (GnRH) agonists are also sometimes

used to suppress ovarian androgen production; "add-back" estrogen-progestin
therapy is necessary to avoid bone loss and estrogen deficiency symptoms.
Although this approach is effective, it is limited by its complexity and cost. (See
"Treatment of hirsutism", section on 'Treatments not recommended'.)

Although some clinicians use metformin to treat hirsutism, the Endocrine Society
Clinical Practice Guidelines suggest against its routine use as it is associated with
minimal or no benefit and is less effective than treatment with COCs and/or
antiandrogens [10]. (See "Metformin for treatment of the polycystic ovary syndrome",
section on 'Hirsutism'.)

Hirsutism can also be treated by removal of hair by mechanical means such as

shaving, waxing, depilatories, electrolysis, or laser treatment. In addition, eflornithine
hydrochloride cream (13.9%) is a topical drug that inhibits hair growth. It is not a
depilatory and must be used indefinitely to prevent regrowth. (See "Removal of
unwanted hair" and "Treatment of hirsutism", section on 'Direct hair removal
methods'.)

Acne and androgenetic alopecia — The management of acne and scalp hair loss
(androgenetic alopecia) in women with PCOS are reviewed in detail separately. (See
"Treatment of acne vulgaris", section on 'Hormonal therapy' and "Treatment of
androgenetic alopecia in men".)

Metabolic abnormalities

Obesity — Weight loss, which can restore ovulatory cycles and improve metabolic
risk, is the first-line intervention for most women. The approach to obesity
management is the same as that for patients without PCOS, starting with lifestyle
changes (diet and exercise) [11], followed by pharmacotherapy, and, when
necessary, bariatric surgery [12]. (See 'Weight reduction' below and "Obesity in
adults: Overview of management" and "Outcomes of bariatric surgery", section on
'Polycystic ovary syndrome'.)

Weight reduction — We suggest weight-loss strategies using calorie-restricted

diets combined with exercise for women with PCOS and obesity. Although there are
no large randomized trials of exercise-specific interventions, a systematic review of
exercise therapy in PCOS concluded that there may be modest weight loss and
improvements in ovulation and insulin sensitivity [13]. (See "Obesity in adults: Role
of physical activity and exercise", section on 'Adding exercise to diet only minimally
beneficial for weight loss' and "Obesity in adults: Dietary therapy".)

Even modest weight loss (5 to 10 percent reduction in body weight) in women with
PCOS may result in restoration of normal ovulatory cycles [14-16] and improved
pregnancy rates [17] in short-term studies. However, the response to weight loss is
variable; not all individuals have restoration of ovulation or menses despite similar
weight reduction [11,12,18]. In addition, there are no randomized trials and no long-
term data on reproductive or metabolic outcomes with weight loss.
Weight loss results in a decrease in serum androgen concentrations and, in some
instances, improvements in hirsutism. However, data demonstrating an improvement
in hirsutism are limited [3,11].

There is no good evidence that one type of diet is superior to another for women with
PCOS. Low-carbohydrate diets have become very popular for women with PCOS,
based upon the notion that less carbohydrate leads to less hyperinsulinemia and
therefore less insulin resistance. However, a 12-week study of a high protein/low
carbohydrate diet (30 percent protein, 40 percent carbohydrate, 30 percent fat) and a
low protein/high carbohydrate diet (15 percent protein, 55 percent carbohydrate, 30
percent fat) were equally effective for weight loss, improvements in menstrual
cyclicity, insulin resistance, dyslipidemia, and abdominal fat in one study of 28
overweight women with PCOS [19]. It is not known if an extremely low carbohydrate
diet would be any more effective for these endpoints. (See "Obesity in adults: Dietary
therapy", section on 'Low-carbohydrate diets'.)

Bariatric surgery — Bariatric surgery is another strategy for weight loss in women
with PCOS. In one study of 17 obese women with PCOS with a mean body mass
index (BMI) of 50.7 kg/m2, bariatric surgery was associated with a mean weight loss
after 12 months of 41±9 kg, restoration of ovulatory cycles, and improvements in
insulin resistance, hyperandrogenemia, and hirsutism scores [12]. A retrospective
chart review and meta-analysis of 29 studies reported similar benefits for women
with PCOS [20,21]. (See "Bariatric operations for management of obesity: Indications
and preoperative preparation" and "Outcomes of bariatric surgery", section on
'Polycystic ovary syndrome'.)

Insulin resistance/type 2 diabetes — Several drugs, including biguanides

(metformin) and thiazolidinediones (pioglitazone, rosiglitazone), can reduce insulin
levels in women with PCOS. These drugs may also reduce ovarian androgen
production (and serum free testosterone concentrations) and restore normal
menstrual cyclicity [22-25]. (See "Metformin for treatment of the polycystic ovary
syndrome" and "Thiazolidinediones in the treatment of diabetes mellitus".)
Although there had been widespread enthusiasm and use of metformin for a number
of indications in PCOS, clinical data no longer support this approach. A detailed
discussion of metformin use in PCOS is found elsewhere. (See "Metformin for
treatment of the polycystic ovary syndrome".)

Strategies recommended by the American Diabetes Association (ADA) for

prevention of type 2 diabetes are discussed separately. The approach in women with
PCOS is the same as for women without PCOS. (See "Prevention of type 2 diabetes
mellitus".)

Thiazolidinediones have been less well studied than metformin, but they appear to
improve insulin sensitivity and hyperandrogenemia [22-28]. However, because of
limited clinical data, potential weight gain, and a possible association with
cardiovascular adverse events, we do not recommend the use of thiazolidinediones
in women with PCOS who do not have diabetes. (See "Thiazolidinediones in the
treatment of diabetes mellitus".)

Though not specifically approved for PCOS, liraglutide is approved for individuals
with a BMI of 30 kg/m2 or greater. Limited data in women with PCOS suggest that
liraglutide results in greater weight loss than placebo [29,30]. (See "Obesity in adults:
Drug therapy", section on 'Liraglutide'.)

Metabolic effects of COCs in PCOS — In healthy women, combined estrogen-

progestin oral contraceptive (COC) use decreases insulin sensitivity, but in general,
this decrease is not clinically significant [31]. It has been assumed that COC use
would also worsen insulin sensitivity in women with PCOS, although data are
conflicting, with studies showing an improvement [32], worsening [33], or no change
[34] in insulin sensitivity. When compared with metformin, COCs may be less
beneficial for insulin sensitivity, but better for androgen suppression and menstrual
cycle control [35]. This topic is reviewed separately.

There are also theoretical concerns that women with PCOS may be at particular risk
for cardiovascular complications with COCs, given their other underlying
cardiovascular risk factors. However, there are no COC risk data specific to women
with PCOS. (See "Combined estrogen-progestin contraception: Side effects and
health concerns", section on 'Cardiovascular effects'.)

The effects of combination COC-metformin therapy are reviewed elsewhere. (See

"Metformin for treatment of the polycystic ovary syndrome", section on 'Adding
metformin to oral contraceptives'.)

Dyslipidemia — The approach to treatment of dyslipidemia in women with PCOS is

the same as for other patients with dyslipidemia. Exercise and weight loss are the
first-line approach, followed by pharmacotherapy, if needed. (See "Statins: Actions,
side effects, and administration".)

Statins — Statins are effective for dyslipidemia in women with PCOS but do not
appear to have other clinically important metabolic or endocrine effects. In a meta-
analysis of four trials in 244 women randomly assigned to a statin (simvastatin or
atorvastatin) or placebo for 6 to 12 months, statin therapy decreased serum low-
density lipoprotein (LDL) and triglycerides, but had no effect on high-density
lipoprotein (HDL), fasting insulin, or C-reactive protein. A small decrease in serum
testosterone was observed, but there were no improvements in menstrual cycle
regularity, ovulation, acne, hirsutism, or BMI [36].

Obstructive sleep apnea — Sleep apnea, a common disorder in women with

PCOS, is an important determinant of insulin resistance, glucose intolerance, and
type 2 diabetes (see "Clinical manifestations of polycystic ovary syndrome in
adults"). In one report of women with PCOS and obstructive sleep apnea, treatment
with continuous positive airway pressure (CPAP) improved insulin sensitivity and
reduced diastolic blood pressure [37]. Similar benefit was reported in a meta-
analysis of eight studies [38].

Nonalcoholic steatohepatitis — The prevalence of nonalcoholic steatohepatitis

(NASH) appears to be increased in women with PCOS. Both weight loss and
metformin use appear to improve metabolic and hepatic function in these women
[39,40]. (See "Clinical manifestations of polycystic ovary syndrome in adults", section
on 'Nonalcoholic fatty liver disease'.)
Depression/anxiety — There is evidence that women with PCOS have impaired
quality of life and higher rates of depression and anxiety when compared with
women of similar BMI without PCOS [41]. However, the efficacy and safety of
antidepressant therapy has not yet been established in women with PCOS and
anxiety or depression [42]. (See "Clinical manifestations of polycystic ovary
syndrome in adults", section on 'Psychosocial issues' and "Diagnosis of polycystic
ovary syndrome in adults", section on 'Depression and anxiety disorders'.)

WOMEN PURSUING PREGNANCY

Weight loss — For anovulatory women with PCOS who are overweight or obese,
we suggest weight loss prior to initiating ovulation induction therapy. The approach
to obesity management is the same as that for patients without PCOS, starting with
lifestyle changes (diet and exercise) [11], followed by pharmacotherapy (if not
pursuing pregnancy), and, when necessary, bariatric surgery [12]. (See 'Weight
reduction' above and "Obesity in adults: Overview of management" and "Outcomes
of bariatric surgery", section on 'Polycystic ovary syndrome'.)

Even modest weight loss of 5 to 10 percent has been associated with an

improvement in metabolic status [43], a reduction in serum androgen concentrations,
and resumption of ovulation in some studies [11,12,14-19,44,45]. Not all women
develop ovulatory cycles despite similar degrees of weight loss [11,12,16,18]. In
addition, data on pregnancy rates and outcomes have been limited [3].

However, a post hoc comparison of two multicenter, concurrent trials in

overweight/obese women with PCOS and anovulatory infertility reported higher
ovulatory and live birth rates with pretreatment lifestyle modification and weight loss
when compared with immediate treatment with clomiphene citrate [46]. The two
concurrent trials included:

●
 The Treatment of Hyperandrogenism versus Insulin Resistance in Infertile
Polycystic Ovary Syndrome (OWL-PCOS) Women, an open-label study of
overweight or obese women with PCOS and anovulatory infertility assigned to
16 weeks of pretreatment with continuous oral contraceptives (COCs; n = 47),
lifestyle modification (including caloric restriction, antiobesity medication,
behavioral medication, and exercise; n = 48), or the combination of both (COCs
and lifestyle; n = 47) followed by up to four cycles of clomiphene citrate for
ovulation induction.
●

Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial (n = 187), a double-

blinded trial of up to five cycles of clomiphene or letrozole. Data was extracted
only from patients in the clomiphene treatment group who met the body mass
index (BMI) criteria for the OWL-PCOS study. Only the first four clomiphene
cycles were analyzed.

In PPCOS II, after four cycles of clomiphene (with no pretreatment), the cumulative
per-cycle ovulatory and live birth rates were 45 and 10.2 percent; (227 of 619 cycles,
19 of 187 patients). In OWL-PCOS, a 16-week pretreatment lifestyle intervention
resulted in an approximate 6.5 percent weight loss from baseline and improvements
in ovulatory and live birth rates (62 and 25 percent, respectively; 80 of 129 cycles
and 12 of 48 patients). Pretreatment with oral contraceptives (alone or combined
with lifestyle intervention) did not affect outcomes.

Although we encourage weight loss in obese woman with PCOS and anovulatory
infertility, our approach is somewhat different in older women (≥37 years) or in those
whose testing shows diminished ovarian reserve. In these settings, we typically offer
either immediate ovulation induction or a short (three-month) attempt at weight loss
followed by ovulation induction. We do not suggest a longer attempt to lose weight.

Ovulation induction medications

●
For oligoovulatory women with PCOS undergoing ovulation induction, we now
suggest letrozole as first-line therapy over clomiphene citrate, regardless of the
patient's BMI. Before starting letrozole, the clinician must discuss that this use
of the drug is not approved by the US Food and Drug Administration (FDA) for
this purpose and that there is an available alternative (clomiphene citrate). (See
"Ovulation induction with letrozole", section on 'Outcomes'.)
●

Clomiphene citrate had been the first-line drug for this population for many
years, with metformin used as an alternative. However, both clomiphene and
metformin appear to be less effective for live birth rates than letrozole [47]. In
women with PCOS, an ovulatory rate of 80 percent and a cumulative pregnancy
rate of 30 to 40 percent can be expected. Cumulative pregnancy rate is
dependent on patient BMI, with higher BMI levels associated with lower
cumulative pregnancy rate. (See "Ovulation induction with clomiphene citrate".)
●

A multistep approach to the management of anovulatory infertility in women with

PCOS is shown in the table (table 2). (See "Ovulation induction with letrozole".)
●

Metformin – Metformin is a drug whose major effect is to reduce hepatic glucose

output and thereby lower serum insulin concentrations. Metformin has been
used to promote ovulation either alone or in combination with clomiphene, but
clomiphene or letrozole monotherapy appears to be superior to metformin
monotherapy on live birth rates. Its role in treating infertility is limited [1]. Clinical
trial data supporting this are reviewed elsewhere. (See "Metformin for treatment
of the polycystic ovary syndrome", section on 'Anovulatory infertility'.)
Current guidelines recommend against the routine use of metformin in obese
women with PCOS (including ovulation induction), except in women with
glucose intolerance who have failed lifestyle interventions [1,48]. Metformin
therapy for PCOS and strategies for prevention of type 2 diabetes are discussed
in more detail separately. (See "Metformin for treatment of the polycystic ovary
syndrome" and "Prevention of type 2 diabetes mellitus".)
●

Gonadotropin therapy – Another method to induce ovulation is administration

of exogenous gonadotropins [49]. A study of 225 women with PCOS treated
over a 10-year period at one center found rates of ovulation and pregnancy of
72 percent and 45 percent, respectively, after the administration of low-dose
gonadotropins [50]. Exogenous gonadotropin therapy is reviewed in detail
elsewhere. Women with PCOS and anovulatory infertility treated with
gonadotropins are at high risk for ovarian hyperstimulation syndrome (OHSS).
Exogenous gonadotropin regimens are complex and expensive and are best
carried out by experienced clinicians; most clinicians recommend an
assessment of fallopian tube patency before initiating these relatively aggressive
therapies. (See "Pathogenesis, clinical manifestations, and diagnosis of ovarian
hyperstimulation syndrome" and "Prevention of ovarian hyperstimulation
syndrome" and "Overview of ovulation induction".)
●

Other medications
•
Thiazolidinedione therapy has been investigated for induction of ovulation
[8,51-53], but we do not suggest its use because of concern about its
cardiovascular safety. (See 'Insulin resistance/type 2 diabetes' above and
"Thiazolidinediones in the treatment of diabetes mellitus".)
•
Although women with PCOS are not likely gonadotropin-releasing hormone
(GnRH) deficient, pulsatile GnRH is moderately effective for ovulation
induction. It is currently available in Europe, but not in the United States. In
one study of 41 patients undergoing 114 ovulation induction cycles, 56
percent of women ovulated, and 40 percent of ovulatory patients achieved
pregnancy [54]. Ovulatory cycles were associated with lower BMI and
fasting insulin, and higher baseline serum follicle-stimulating hormone
(FSH) concentrations. Thus, pulsatile GnRH may be a reasonable option,
particularly for lean women with PCOS.
Acupuncture — Infertility centers often offer acupuncture as an adjunctive therapy
to women with PCOS undergoing ovulation induction or in vitro fertilization. However,
available evidence suggests that it does not improve live birth rates when used alone
or combined with clomiphene citrate (compared with sham acupuncture alone or with
clomiphene) [55,56]. The addition of acupuncture during in vitro fertilization cycles
does not improve outcomes. (See "In vitro fertilization".)

Laparoscopic surgery — In the past, wedge resection of the ovaries was a

standard treatment for infertility in women with PCOS. However, this approach has
been abandoned, both because of the efficacy of clomiphene and because of the
high incidence of pelvic adhesions seen with wedge resection. A substitute for
wedge resection, laparoscopic ovarian laser electrocautery, may be effective in
some women with PCOS. However, given the other pharmacologic options for
ovulation induction, surgery is not often indicated.

For women who do not respond to ovulation induction with either letrozole or
clomiphene citrate, laparoscopic ovarian drilling (also referred to as laparoscopic
ovarian diathermy or electrocoagulation) is a surgical option for second-line
treatment. When compared with gonadotropin therapy, another second-line
treatment, ovarian drilling has similar efficacy but results in lower risk of high order
multiple gestations or OHSS (table 3) [57,58]. Disadvantages of ovarian drilling
include surgical risk and potential adhesion formation. Although laparoscopic ovarian
drilling has been utilized for decades, the technique has never been standardized
regarding the energy source, number of punctures, dose and duration per puncture,
or whether one or both ovaries should be treated. Based on limited dose-ranging
studies, three to six punctures per ovary at 40 W of coagulating (modulated) current
for four seconds per puncture seems reasonable [59,60].

Ovarian drilling likely reduces ovarian secretion of androgens and proteins, resulting
in an increase in LH and FSH secretion. In turn, following ovarian drilling, the ovary
is more responsive to stimulation by endogenous gonadotropins favoring the growth
of a dominant ovarian follicle and ovulation. Following ovarian drilling ovulatory
cycles occur in approximately 80 percent of patients with a range of 30 to 90 percent,
in published studies [61]. The normalization of ovulatory function continued for many
years in the majority of patients following ovarian drilling [62-65].

In vitro fertilization — If weight loss, ovulation induction with medications, and/or

laparoscopic ovarian laser electrocautery are unsuccessful, the next step is in vitro
fertilization. Without co-interventions, women with PCOS are at increased risk for
both multiple gestation and OHSS. Women with PCOS who undergo in vitro
fertilization have lower rates of OHSS. However, the risk of OHSS is decreased with
the transfer of frozen rather than fresh embryos in these women. Metformin
administration may also help to reduce the risk of OHSS in women with PCOS. (See
"In vitro fertilization", section on 'Women with polycystic ovary syndrome (PCOS)'.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and

regions around the world are provided separately. (See "Society guideline links:
Polycystic ovary syndrome" and "Society guideline links: Hirsutism".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond
the Basics." The Basics patient education pieces are written in plain language, at the
5th to 6th grade reading level, and they answer the four or five key questions a patient
might have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage
you to print or e-mail these topics to your patients. (You can also locate patient
education articles on a variety of subjects by searching on "patient info" and the
keyword(s) of interest.)

Basics topics (see "Patient education: Polycystic ovary syndrome (The Basics)")
●

Beyond the Basics topics (see "Patient education: Polycystic ovary syndrome
(PCOS) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Regardless of the diagnostic criteria used, the management of polycystic ovary

syndrome (PCOS) includes treatment of individual components of the syndrome
(hirsutism, oligomenorrhea, infertility, obesity, and glucose intolerance), depending
upon the patient's goals.

Weight loss, which can improve metabolic risk, restore ovulatory cycles and
possibly improve live birth rates, is the first-line intervention for most women.
(See 'Overview of approach' above and 'Weight loss' above.)
●

Combined estrogen-progestin oral contraceptives (COCs) are the mainstay of

pharmacologic therapy for women with PCOS for managing hyperandrogenism
and menstrual dysfunction and for providing contraception.
●

Our approach to the use of COCs in women with PCOS is the same as that for
women without PCOS. Risk factors for venous thromboembolism (VTE),
including obesity, patient age, and family history of VTE, should be assessed.
More information can be found in the Centers for Disease Control and
Prevention (CDC) United States Medical Eligibility Criteria for Contraceptive
Use.
We suggest caution when prescribing COCs in obese women (body mass index
[BMI] ≥30 kg/m2) over age 40 years because of their greater risk of VTE. Other
relative and absolute contraindications to COC use are outlined in the CDC
United States Medical Eligibility Criteria for Contraceptive Use. (See 'Oral
contraceptives and risk assessment' above.)
●

For hirsutism or other androgenic manifestations, we suggest a COC as the

treatment of choice (Grade 2B). (See 'Androgen excess' above.)
●

We typically start with a COC containing 20 mcg of ethinyl estradiol combined

with a progestin such as norethindrone or norethindrone acetate, progestins that
have lower androgenicity, but similar VTE risk compared with levonorgestrel-
containing COCs. Higher doses of ethinyl estradiol are needed in some women
for optimal management of hyperandrogenic symptoms. Concerns about VTE
risk with newer progestins and with drospirenone are reviewed separately. (See
'Choice of oral contraceptive' above and "Combined estrogen-progestin
contraception: Side effects and health concerns", section on 'Venous
thromboembolism'.)
●

If the patient is not satisfied with the clinical response to six months of COC
monotherapy (for hyperandrogenic manifestations), we suggest adding
spironolactone (Grade 2B). (See 'Androgen excess' above and "Treatment of
hirsutism".)
●

For prevention of endometrial hyperplasia and possibly cancer, we suggest

COC therapy (Grade 2C). (See 'Menstrual dysfunction' above.)
●

For women with PCOS who choose not to or cannot take COCs, we typically
use intermittent progestin therapy. (See 'Menstrual dysfunction' above.)
●
For women with PCOS undergoing ovulation induction, we now suggest
letrozole as first-line therapy over clomiphene citrate (Grade 2B). Before starting
letrozole, the clinician must discuss that this use of the drug is not approved by
the US Food and Drug Administration (FDA) and that clomiphene is an
alternative. (See "Ovulation induction with letrozole", section on 'Suggested
approach'.)
●

For women with PCOS and a BMI >30 kg/m2, we also suggest diet and exercise
to promote weight loss. (See 'Women pursuing pregnancy' above.)