Use of clomiphene citrate in women
The Practice Committee of the American Society for Reproductive Medicine
American Society for Reproductive Medicine, Birmingham, Alabama
Ovulatory dysfunction is one of the most common causes of
over consecutive cycles of treatment, but there is no evi-
reproductive failure in sub-fertile and infertile couples. In the
dence of any important clinical consequence
absence of other significant infertility factors, successfulovulation induction often will restore normal fertility. Clo-miphene citrate (CC) is the best initial treatment for the large
MODE OF ACTION
majority of anovulatory infertile women. The first clinical
Structural similarity to estrogen allows CC to bind to estro-
trial of CC therapy demonstrated successful ovulation induc-
gen receptors (ER) throughout the reproductive system.
tion in 80% of women, half of whom achieved pregnancy
However, in contrast to estrogen, CC binds nuclear ER for an
during treatment In subsequent years, results of CC
extended period of time and ultimately depletes ER concen-
treatment have not changed appreciably, despite the advent
trations by interfering with the normal process of ER replen-
of modern immunoassays for steroid hormones, advances in
ishment The drug’s effectiveness in ovulation induction
ultrasound technology for cycle monitoring, and the intro-
can be attributed to actions at the hypothalamic level. De-
duction of commercial test kits that allow detection of the
pletion of hypothalamic ER prevents correct interpretation of
midcycle luteinizing hormone (LH) surge in urine.
circulating estrogen levels. Reduced levels of estrogen neg-ative feedback trigger normal compensatory mechanisms
This guideline will first describe the pharmacology, mode
that alter pulsatile hypothalamic GnRH secretion to stimu-
of action, and indications for CC treatment. Second, it will
late increased pituitary gonadotropin release that, in turn,
outline the pretreatment evaluation, standard and combina-
drives ovarian follicular activity. In ovulatory women, CC
tion treatment regimens, and alternative strategies for the
treatment increases GnRH pulse frequency In anovula-
CC-resistant patient. Lastly, it will summarize the methods
tory women with polycystic ovary syndrome (PCOS) in
for monitoring therapy and review the results, side effects,
whom the GnRH pulse frequency is already abnormally
high, CC treatment increases pulse amplitude, but not fre-quency During CC treatment, levels of both LH and FSH
rise, falling again after the typical 5-day course of therapy is
Chemically, CC (like tamoxifen) is a nonsteroidal triphenyleth-
completed In successful treatment cycles, one or more
ylene derivative that exhibits both estrogen agonist and antag-
dominant follicles emerge and mature, generating a rising
onist properties In general, estrogen agonist properties are
tide of E that ultimately triggers the midcycle LH surge and
manifest only when endogenous estrogen levels are extremely
low. Otherwise, CC acts solely as a competitive estrogen
Not surprisingly, tamoxifen also has been used success-
antagonist. Clomiphene citrate is cleared through the liver
fully to induce ovulation in anovulatory infertile women
and excreted in stool. About 85% of an administered dose is
Given its structural similarity to CC, its mechanism of action
eliminated after approximately 6 days, although traces may
presumably is also similar Recent evidence suggests
remain in the circulation for much longer As currently
that letrozole, an orally active aromatase inhibitor, may have
manufactured, CC is a racemic mixture of two distinct ste-
potential as an ovulation-inducing agent In contrast
reoisomers, enclomiphene and zuclomiphene. Available ev-
to the central actions of CC and tamoxifen, letrozole acts in
idence indicates that enclomiphene is the more potent isomer
the periphery to inhibit ovarian follicular E production, but
and the one primarily responsible for the ovulation inducing
the end result is similar—a decrease in central estrogen
actions of CC Enclomiphene levels rise rapidly after
feedback action that stimulates a compensatory increase in
administration and fall to undetectable concentrations soon
thereafter. Zuclomiphene is cleared far more slowly. Levelsof this less active isomer remain detectable in the circulationfor more than a month after treatment and may accumulate
The causes of anovulation are many and varied. Whenever
Reviewed June 2006.
possible, treatment should be directed at correcting the un-
Received June 20, 2003; and accepted June 20, 2003.
derlying cause. Correct diagnosis may suggest specific treat-
ment, and many conditions may have longer-term health
Correspondence to: Practice Committee, American Society for Repro-
consequences. Thyroid disease, pituitary tumors, eating dis-
ductive Medicine, 1209 Montgomery Highway, Birmingham, Alabama35216.
orders, extremes of weight loss and exercise, hyperpro-
Fertility and Sterilityா Vol. 86, Suppl 4, November 2006 S187
Copyright 2006 American Society for Reproductive Medicine, Published by Elsevier Inc.
lactinemia, PCOS, and obesity may be identified, but very
Acanthosis nigricans is often observed in women with un-
often the immediate cause of anovulation cannot be confi-
derlying insulin resistance or frank diabetes and merits for-
dently defined. CC is the initial treatment of choice for most
mal evaluation to exclude these diagnoses Screening
anovulatory or oligo-ovulatory infertile women. However,
for hypothyroidism (serum TSH) and hyperprolactinemia
given its hypothalamic site of action, CC is often ineffective
(serum prolactin) is reasonable since both disorders are best
in women with hypogonadotropic hypogonadism (hypotha-
treated with medications other than CC Hirsutism
lamic amenorrhea). Women with other demonstrable endo-
that is severe or rapid in progression warrants specific addi-
crinopathies (diabetes mellitus, thyroid disorders, hyperpro-
tional evaluation to exclude non-classic congenital adrenal
lactinemia, congenital adrenal hyperplasia) should first
hyperplasia (CAH) and androgen-producing tumors of the
receive specific treatment and be offered CC only when that
therapy fails to restore regular ovulatory cycles.
Attempts at ovulation induction are generally futile in women
with elevated serum FSH levels. Those with hypothalamic/
Luteal Phase Deficiency
pituitary dysfunction are also unlikely to respond to CC as its
Given that the corpus luteum derives from the follicle that
mechanism of action requires a functional hypothalamic/
ovulates, its functional capacity is, at least in part, dependent
pituitary/ovarian feedback axis. Alternative treatments that
on the quality of preovulatory follicle development. In that
will reestablish normal hypothalamic/pituitary communication
context, CC is one logical treatment option for luteal phase
(pulsatile exogenous GnRH) or stimulate the ovary directly
deficiency (LPD) Progesterone levels are typically
(exogenous gonadotropins) will generally be required.
higher after CC treatment than in spontaneous cycles, re-flecting improved preovulatory follicle and corpus luteum
Ovulation induction has little value when severe male,
development and/or the combined hormone production of
uterine, or tubal factors are also present. Semen analysis
should be performed to identify seminal abnormalities thatalso may require treatment. Hysterosalpingography is indi-cated when clinical history raises suspicion of uterine or
tubal pathology (pelvic infection or surgery, ectopic preg-
In couples whose infertility remains unexplained after care-
nancy, inflammatory bowel disease), but may otherwise be
ful and thorough evaluation, empiric treatment with CC may
reserved for those who fail to conceive within three to six
be justified, particularly in young couples with a short du-
ovulatory treatment cycles. An HSG is also prudent in older
ration of infertility and in those unwilling or unable to pursue
women (over 35 years) to avoid ineffective treatment at a
more aggressive therapies involving greater costs, risks, and
time when fertility is steadily declining.
logistical demands The efficacy of empiric CCtreatment may be attributed to correction of subtle and un-recognized ovulatory dysfunction and/or “superovulation” of
more than a single ovum CC treatment is most effective
when it is combined with properly timed intrauterine insem-
CC is administered orally, typically starting on the third to fifth
ination (IUI), all in an effort to bring together more than the
day after the onset of spontaneous or progestin-induced menses;
usual numbers of ova and sperm at the optimal time
ovulation rates, conception rates, and pregnancy outcome aresimilar regardless whether treatment begins on cycle day 2,
3, 4, or 5 Although the dose required to achieve
Infertile women who rarely or never ovulate are candidates
ovulation correlates with body weight, there is no reliable
for CC treatment. Diagnosis of ovulatory dysfunction may
way to accurately predict what dose will be required in an
individual woman Consequently, CC induction of ovu-lation amounts to an empiric incremental titration in efforts
to establish the lowest effective dose for each individual.
● Timed serum P determinations● Monitoring urinary LH excretion
Treatment typically begins with a single 50-mg tablet
daily for 5 consecutive days, increasing by 50-mg incre-
● Serial transvaginal ultrasound examinations
ments in subsequent cycles until ovulation is induced. Theeffective dose of CC ranges from 50 mg/day to 250 mg/day,
However, specific tests of ovulation are unnecessary when
although doses in excess of 100 mg/day are not approved by
menstrual history alone is diagnostic (amenorrhea, oligo-
the Food and Drug Administration (FDA). Lower doses
menorrhea). Once identified, anovulatory infertile women
(e.g., 12.5 mg/day to 25 mg/day) deserve a trial in women
merit additional pretreatment evaluation to identify any un-
who demonstrate exquisite sensitivity to CC or consistently
derlying systemic illness that may require additional tests,
develop large ovarian cysts that interfere with efficient cyclic
treatment Most women ovulate in response to treatment
A detailed medical history and physical examination may
with 50 mg (52%) or 100 mg (22%); higher doses have been
reveal evidence of other endocrine or metabolic disease.
used, but also are less often successful (150 mg, 12%; 200
Use of clomiphene citrate in women
mg, 7%; 250 mg, 5%) Some CC-resistant anovulatory
domized trials have demonstrated that IUI after exogenous
women who fail to respond to a standard 5-day treatment
hCG-triggered ovulation in CC-induced cycles is no more
regimen may respond to longer courses (8 days) of CC
effective than IUI performed after detection of the endoge-
treatment but such treatment should be considered only
nous LH surge Therefore, use of exogenous hCG is
when alternative treatment with exogenous gonadotropins is
perhaps best limited to those women who require IUI and in
whom a midcycle LH surge cannot reliably be detected.
Clomiphene and Glucocorticoids
In some CC-resistant
Alternative and Combination Treatment Regimens
PCOS women, addition of glucocorticoids (e.g., dexameth-asone 0.5 mg or prednisone 5 mg hs) to the CC treatment
Many women who prove resistant or refractory to standard
regimen may induce ovulation when CC alone has failed
CC treatment may ovulate in response to alternative treat-
Adjunctive glucocorticoid treatment may be based on
ment regimens. A choice among them should not be arbi-
the serum DHEAS concentration (Ͼ200 g/dL) or
trary, but based on specific elements of the patient’s history,
empiric Treatment may be continued (three to six
results of laboratory evaluation, and/or observations in pre-vious unsuccessful CC treatment cycles. These regimens
cycles) when it is successful and should be promptly discon-
also should not be considered as a prerequisite for use of
tinued when it is not. There is no evidence that glucocorti-
more aggressive treatment strategies (e.g., exogenous gonad-
coid treatment has any important side effects or risks when
otropins). They are merely useful alternatives that merit
used in the doses or for the duration indicated.
consideration, depending on the patient’s age, goals, avail-
Clomiphene and Gonadotropins
women who ultimately require exogenous gonadotropins to
Insulin Sensitizing Agents
Insulin resistance and hyperinsu-
achieve ovulation and those with unexplained infertility might
linemia are common features in women with PCOS. Most
benefit from a trial of sequential CC/gonadotropin therapy
women with PCOS will respond to CC, but many prove
using either traditional menotropins (hMG) or purified or re-
resistant and ultimately require alternative treatment. Among
combinant FSH Given the costs and risks of exogenous
these, a large majority will have demonstrable insulin resis-
gonadotropin therapy, treatment should be offered only by
tance Insulin sensitizing agents (e.g., metformin) alone
those having the requisite training or experience. The typical
can restore menses and cyclic ovulation in many amenor-
cycle includes a standard CC treatment regimen (50 mg/day to
rheic PCOS women although they are not currently
100 mg/day, cycle days 5–9), followed by low-dose hMG or
approved by the FDA for this indication. Based on observa-
FSH (75 IU/day, cycle days 9 –12). Treatment is individual-
tions from open trials, some advocate metformin as primary
ized thereafter, in the same way as with traditional gonado-
therapy in anovulatory infertile PCOS women (1,000 mg/day
tropin therapy, based on transvaginal ultrasound examina-
to 2,000 mg/day in divided doses) and add CC only in those
tions. Cycle fecundity with this approach is similar to that
who fail to respond Given the greater costs and com-
achieved with gonadotropins alone, but the dose and dura-
plexity of metformin treatment and the frequency of severe
tion of treatment and the associated costs of monitoring may
gastrointestinal side effects (e.g., nausea, vomiting, diar-
be significantly reduced. Treatment with exogenous gonad-
rhea), others prefer to reserve metformin treatment for those
otropins alone is the obvious alternative. CC-resistant anovu-
who first prove resistant to CC. In either case, many who fail
latory women are often very sensitive to low doses of go-
to ovulate in response to either alone will respond when the
nadotropins and treatment should be aimed at achieving
two are used in combination Because metformin
ovulation of but a single mature follicle if possible. There is
therapy may have hepatic toxicity or be complicated by
no indication for purposeful superovulation in the anovula-
lactic acidosis, liver and renal functions must be evaluated
before treatment and monitored periodically thereafter. Al-
A contemporary version of the classic
though the safety of metformin treatment in pregnancy has
ovarian wedge resection is another treatment option in CC-
not been established, preliminary evidence suggests that it
resistant, hyperandrogenic, anovulatory women (e.g., PCOS).
may reduce the incident risk of spontaneous abortion and
The technique involves laparoscopic cautery, diathermy, or
laser vaporization of the ovaries at multiple sites, the objective
Clomiphene and hCG
Although exogenous hCG has been
being to decrease circulating and intraovarian androgen lev-
used to trigger ovulation and define the optimal time to
els by reducing the volume of ovarian stroma. Data derived
perform IUI in CC-induced cycles, the practice is difficult to
from randomized controlled trials suggest that initial ovula-
justify on a routine basis. Treatment requires costly moni-
tion and pregnancy rates after ovarian drilling are similar to
toring with serial transvaginal ultrasound examinations that
those achieved by treatment with exogenous gonadotropins,
are otherwise unnecessary. The mean peak diameter of the
and the risk of multiple pregnancy is lower When it
preovulatory follicle in successful CC-induced ovulatory
does not result in spontaneous ovulation, ovarian drilling
cycles ranges between 19 and 30 mm (median diameter: 25
may help to restore sensitivity to CC treatment. Ovarian
mm) and the optimum time to administer hCG is
drilling is a reasonable option for clomiphene-resistant
therefore difficult to determine. Most importantly, two ran-
anovulatory women, but the temporary effects of treatment
FERTILITY & STERILITY
and the risks of postoperative adhesions or diminished ovar-
Results of Treatment
ian reserve should be carefully considered.
CC treatment will successfully induce ovulation in approx-imately 80% of properly selected candidates. Likelihood ofresponse declines with increasing age, body mass index
(BMI), and free androgen index Overall, cycle fecun-
Objective evidence of ovulation and normal luteal function
dity is approximately 15% in anovulatory women who re-
is key to successful treatment. Ovulation can be documented
spond to treatment. In the absence of any other infertility
using any one of a number of methods. The choice may vary
factors, cycle fecundity is higher (22%), and comparable to
and should be tailored to meet the needs of the individual
that seen in fertile women after discontinuation of diaphragm
contraception (25%) and in those with male factor infertilitywho receive inseminations with donor sperm. Approxi-
Basal body temperature (BBT) recordings provide a simple
mately 70% to 75% of anovulatory women who respond to
and inexpensive method for evaluating response to treatment,
CC (50 mg/day to 150 mg/day, as required) may be expected
but may be tedious. Test kits that can identify the midcycle LH
to conceive within six to nine cycles of treatment
surge in urine more precisely define both the interval of peak
Amenorrheic women are more likely to conceive than oli-
fertility and luteal phase duration The surge is typically
gomenorrheic women, probably because those who already
observed between 5 and 12 days after treatment is completed,
ovulate albeit inconsistently, are more likely to have
most often on cycle day 16 or 17 when CC is administered on
other co-existing infertility factors. In infertile women with
days 5–9 Whereas any P level greater than 3 ng/mL
luteal phase deficiency, CC treatment increases luteal phase
provides presumptive evidence of ovulation a midluteal
phase concentration offers more information regarding the
quality of luteal function. Best results are observed when con-centrations exceed 10 ng/mL
Fecundability declines with advancing age; and prolonged
treatment with CC is unjustified in women in their latter
Endometrial biopsy revealing a secretory endometrium
reproductive years. The failure to conceive within a maxi-
also provides evidence of ovulation. Endometrial “dating”
mum of six CC-induced normal ovulatory cycles is a clear
using established histologic criteria may reveal evidence of
indication to expand the diagnostic evaluation to exclude
LPD although controversies persist regarding the ac-
other infertility factors or to change the overall treatment
curacy of traditional diagnostic criteria. Serial transvaginal
strategy if evaluation is already complete.
ultrasound can reveal the size and number of developing
In randomized trials, cycle fecundity in women with un-
follicles and provide presumptive evidence of ovulation
explained infertility treated with empiric CC has ranged
(progressive follicular growth, sudden collapse of the pre-
from 3.4% to 8.1% The benefits of CC treatment
ovulatory follicle, and an increase in cul-de-sac fluid vol-
alone are relatively small— one additional pregnancy for
ume) and luteinization (loss of clearly defined follicular
every 40 cycles of treatment. Based on observations in
margins and appearance of internal echoes) However,
clinical trials, cycle fecundity in couples with unexplained
because of the cost and logistical demands involved, the
infertility treated with CC/IUI is approximately 8.5% to
method generally is reserved for patients in whom less
9.5%, at least twofold higher than in those who receive no
complicated methods fail to provide the necessary informa-
treatment CC/IUI yields one additional pregnancy
tion. In CC/IUI cycles in couples with unexplained infertil-
ity, transvaginal ultrasound is useful to confirm that treat-ment successfully promotes development of more than onemature follicle. A recent study that compared cycle fecundity
SIDE EFFECTS AND RISKS
in CC-induced cycles monitored with BBT, urinary LH
CC is generally very well tolerated. Some side effects are
excretion, or serial ultrasound examinations could demon-
relatively common, but rarely are they persistent or severe
strate no clear advantage for any one of these methods
enough to threaten completion of the usual 5-day course ornext cycle of treatment. Although CC treatment does have
In the past, examination to exclude any significant residual
intrinsic risks, they are typically modest and manageable.
ovarian enlargement has been recommended before eachnew treatment cycle. Although it is prudent to postponefurther treatment when symptoms lead to discovery of a
large cyst or grossly enlarged ovaries, clinical studies
Vasomotor flushes (hot flashes) occur in approximately 10%
and accumulated clinical experience suggest that routine
of CC-treated women, but typically abate soon after treat-
“baseline” physical or ultrasound examinations are not al-
ment ends. Mood swings are also common. Visual distur-
ways necessary. Nevertheless, regular contact should be
bances, including blurred or double vision, scotomata, and
maintained to review response to treatment and to ensure
light sensitivity, are generally uncommon (Ͻ2% prevalence)
that any additional evaluation or alternative treatment that
and reversible, although there are isolated reports of persis-
tent symptoms and more severe complications such as optic
Use of clomiphene citrate in women
neuropathy Whenever visual disturbances are identi-
fied, it is prudent to stop treatment and consider alternative
Ovarian Hyperstimulation Syndrome
The incidence of ovar-
methods of ovulation induction. Less specific side effects
ian hyperstimulation syndrome (OHSS) in CC-treated women
include breast tenderness, pelvic discomfort, and nausea, all
is difficult to determine, as definitions of the syndrome vary
observed in 2% to 5% of CC-treated women.
widely among studies. Whereas mild OHSS (moderate ovar-
Numerous studies have suggested that in addition to the
ian enlargement) is relatively common, severe OHSS (mas-
desirable central actions responsible for its efficacy as an
sive ovarian enlargement, progressive weight gain, severe
ovulation inducing agent, CC exerts undesirable and un-
abdominal pain, nausea and vomiting, hypovolemia, ascites,
avoidable adverse antiestrogenic effects in the periphery
(endocervix, endometrium, ovary, ovum, and embryo) that
Two epidemiologic studies published early
explain the “discrepancy” between the ovulation and con-
in the last decade suggested that the risk of ovarian cancer
ception rates observed in CC-treated patients. However,
might be significantly increased in women exposed to ovu-
there is little or no compelling evidence to support these
lation inducing drugs but subsequent studies have
notions. The quality and quantity of cervical mucus produc-
failed to corroborate those findings A recent pooled
tion in CC treatment cycles may sometimes be reduced
analysis of eight case-control studies concluded that neither
but rarely to an extent that risks interference with the effec-
fertility drug use nor use for more than 12 months was
tive capture, survival, or transport of sperm. Limited endo-
associated with invasive ovarian cancer Patients with
metrial proliferation has been observed in some CC-treated
concerns should be counseled that no causal relationship
patients but the effect is minor or not at all evident in the
between ovulation inducing drugs and ovarian cancer has
large majority of women When reduced endome-
been established and no change in prescribing practices is
trial thickness is observed in CC-induced ovulatory cycles,
warranted. In any case, prolonged treatment with CC is
tamoxifen or letrozole may offer an alternative
generally futile and should therefore be avoided.
method for ovulation induction that may avoid this effect.
Although some studies have suggested that fecundity mayrelate to endometrial thickness, others have failed to dem-
SUMMARY AND CONCLUSIONS
onstrate any significant correlation. CC has indeed beenshown to inhibit steroid hormone production by cultured
● CC is the best initial treatment for the majority of women
avian ovine and human granulosa/luteal cells
whose infertility is associated with ovulatory dysfunction
but estrogen and P levels in CC-induced cycles are typically
(anovulation, luteal phase deficiency). Combined with ap-
significantly higher, not lower, than in spontaneous cycles.
propriately timed IUI, CC treatment also increases cycle
Adverse effects of CC on mouse ovum fertilization and
fecundity in couples with unexplained infertility.
embryo development have been demonstrated in vitro
● CC treatment generally should be limited to the minimum
but circulating levels of CC never reach the concentrations
effective dose and to no more than six ovulatory cycles.
required to produce these effects, even after several consec-
Failure to conceive after successful CC-induced ovulation
utive treatment cycles Taken together, available evi-
is indication for further evaluation to exclude other con-
dence and accumulated clinical experience suggest that any
adverse antiestrogenic effects of CC present no significant
● Combination therapies involving CC and other agents (met-
obstacle in the majority of treated women.
formin, glucocorticoids, exogenous gonadotropins) may beeffective when treatment with CC alone fails to induce ovu-lation. Alternative strategies for the CC-resistant woman
Risks and Complications
include treatment with aromatase inhibitors or exogenous
Multifollicular development is relatively
gonadotropins and, in selected patients, ovarian drilling.
common during CC treatment and the risk of multiple ges-
● CC treatment should be monitored (BBT, serum P con-
tation is clearly increased to approximately 8% overall
centration, urinary LH excretion) to ensure its effective-
The overwhelming majority of multiple pregnancies that
result from CC treatment are twin gestations; triplet and
● Side effects of CC treatment are generally mild and well
higher order pregnancies are rare but may occur.
tolerated. The principal risk of CC treatment is an in-
There is no evidence that CC treat-
creased incidence of multifetal gestation (Ͻ10%).
ment increases the overall risk of birth defects or of any oneanomaly in particular
This report was developed under the direction of thePractice Committee of the American Society for Reproductive Medicine as
Early studies suggested that the in-
a service to its members and other practicing clinicians. While this docu-
cidence of spontaneous abortion in pregnancies resulting
ment reflects appropriate management of a problem encountered in the
from CC treatment was increased over that observed in
practice of reproductive medicine, it is not intended to be the only approvedstandard of practice or to dictate an exclusive course of treatment. Other
spontaneous pregnancies. However, a number of more recent
plans of management may be appropriate, taking into account the needs of
studies have described abortion rates that are not different
the individual patient, available resources and institutional or clinical practice
from those observed in spontaneous pregnancies (10% to
limitations. This bulletin was approved by the Practice Committee of the
FERTILITY & STERILITY
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FERTILITY & STERILITY
PAPER A Crash Course for Maintaining Relevance through Ten Arduous Pages of Information and Analysis What a thesis statement should be: generalization .
A thesis statement should be limited and sharply focused .
A thesis statement makes a claim that is
A thesis should state a logical asser that is not a readily available truth but can be proven through the accumula
NORMA REGULADORA DE PRECIOS PÚBLICOS POR UTILIZACIÓN DE INSTALACIONES DEPORTIVAS Y DE LOCALES E INSTALACIONES ESCOLARES MUNICIPALES Artículo 1.- La presente exacción se establece de acuerdo con lo dispuesto en la subsección 2ª, sección 2ª, Capítulo III, Título Primero de la Ley Foral 2/1995, de las Haciendas Locales de Navarra, y en virtud de la autorización contenida en el art. 28 d