International Congress Series 1279 (2005) 3 – 9

www.ics-elsevier.com

WHO-classification of anovulation: background,

evidence and problems
Marc Dhont*
Ghent University Hospital, Department of Obstetrics an dGynaecology,
De Pintelaan 185, B-9000 Ghent, Belgium

Abstract. In the wake of pharmacological advances in the treatment of anovulation more than 30
years ago, the WHO proposed a practical classification of anovulatory states in three groups, based on
the state of gonadotropin and oestrogen secretion. In the meantime, knowledge of the
pathophysiology of anovulation has broadened and both diagnostic and therapeutic facilities have
increased, prompting the question whether this classification is still valid and practically useful. The
simplicity of breaking down all anovulatory states into three categories is the strength and at the same
time the weakness of this classification. The diagnosis of hypogonadotropic and hypo-oestrogenic
anovulation (WHO Group I) and hypergonadotropic anovulation (WHO-Group III) is straightforward
and the advice for treatment in those cases is clear-cut because the underlying etiopathology is
obvious. More problematic, however, is Group II, the so-called normogonadotropic, normo-
oestrogenic cases, which constitute by far the largest group of patients. This group is a mixture of
different hormonal dysfunctions which can primarily originate from diverse glandular and even
extraglandular sources. The most notorious subgroup among them is made up of patients with the
PCO syndrome (PCOS), which in itself is an amalgam of different pathophysiological mechanisms.
Although the therapeutic flow chart resulting from the WHO classification is more or less in line with
the current practice of ovulation induction, the subdivision into three groups according to
gonadotropin and oestrogen levels insufficiently takes into account the complex pathogenesis of
anovulation. I therefore suggest devising a modified classification which reflects both the diverse
etiologies of anovulation and provides a guide to the currently evidence-based therapies. D 2004
Elsevier B.V. All rights reserved.

Keywords: Anovulation; Classification; WHO; Infertility; Treatment

* Tel.: +32 9 240 3792; fax: +32 9 240 3831.

E-mail address: marc.dhont@ugent.be.

0531-5131/ D 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.ics.2004.12.028
4 M. Dhont / International Congress Series 1279 (2005) 3–9

1. Introduction
Absence of ovulation can have multiple etiologies and is almost always manifested by
menstrual disorders such as oligomenorrhoea, primary and secondary amenorrhoea. In
textbooks of gynaecology, the latter terms are generally being used because they are
directly linked to the symptoms of which the patient is complaining. Although these
menstrual disorders result from an ovulatory dysfunction in the majority of cases,
treatment will depend on whether or not the patient wants to get pregnant in the immediate
future. In patients wanting to get pregnant the attention of clinicians will be mainly
focused on the etiology of anovulation to prescribe the most appropriate treatment.
In 1973 the WHO Scientific Group [1] proposed a classification of anovulatory patients
which was meant to provide guidance for ovulation induction (Table 1). This classification
was based on the levels of gonadotropins and oestrogens and is still being used. In the
intervening 30 years diagnostic and therapeutic possibilities have evolved considerably,
hence, one may wonder whether this simple classification is still relevant and of practical
value.

2. Background
The need for a clinical and treatment-oriented classification arose when urinary
gonadotropins became available for ovulation induction about 40 years ago. At this time
the diagnosis of ovulatory disorders was purely descriptive – oligomenorrhoea, primary
and secondary amenorrhoea – and the diagnostic tools were limited to clinical
observation, vaginal cytology, bimanual palpation of the uterus and the ovaries, basal
body temperature and in specialised laboratories, the colorimetric determination of
oestrogens and the bioassay of gonadotropins in 24 h urinary collection. After having
treated several hundred anovulatory patients with exogenous urinary gonadotropins,
Insler and his coworkers from Israel retrospectively analysed the response of patients to
gonadotropin treatment according to the level of gonadotropins, determined by the
mouse uterus test and the presence or lack of endogenous estrogens, mainly determined
by the presence or absence of bleeding after a progestrogen withdrawal test [2]. He
divided his patients into two categories: group I being patients with low gonadotropins

Table 1
WHO classification of infertile women with anovulation (World Health Organization, Technical Report Series,
1973)
Group I
Women with primary or secondary amenorrhoea, low levels of endogenous gonadotropins and negligible
endogenous oestrogen activity (urinary oestrogens usually lower than 10 Ag/24 hr).

Group II
Patients with anovulation associated with a variety of menstrual disorders (including amenorrhoea) who exhibit
distinct endogenous oestrogen activity whose urinary and serum gonadotropins are in the normal range.

Group III
Women with primary or secondary amenorrhoea due to primary ovarian failure associated with low endogenous
oestrogen activity and pathologically high gonadotropin levels.
 M. Dhont / International Congress Series 1279 (2005) 3–9 5

and endogenous estrogens and group II with normal gonadotropins and estrogens. He
found that patients of group I needed more ampules of HMG and that stimulation took
longer than in group II. He also discerned an intermediary group with postpartum
amenorrhoea and galactorrhoea. Based on this preliminary classification the Scientific
Group of the WHO in 1973 added a third group characterised by low oestrogens and
high gonadotrophins, the WHO Group III.
Before serum determination of gonadotropins and oestrogens became generally
available, the biological estimation of oestrogen activity was the mainstay for starting a
diagnostic and therapeutic flow chart in patients with anovulation. Women with
spontaneous, albeit irregular, menstrual bleeding and women who had a withdrawal
bleeding after progesterone were considered to have normal endogenous oestrogen activity
[3]. Because spontaneous or progesterone-induced menstrual bleeding indicates that there is
a basal ovarian activity which in its turn is dependent on a functioning hypothalamo-
pituitary axis, this simple observation allowed the conclusion that the hypothamamic-
pituitary-ovarian axis is in a potentially normal state and that the genital tract is anatomically
and functionally intact. In women with amenorrhoea and no bleeding after progesterone the
level of gonadotropins could differentiate between ovarian failure (high level of
gonadotropins) and hypothalamic-pituitary insufficiency (low level of gonadotropins). A
uterine factor could be excluded by a sequential treatment with oestrogens and progesterone;
if a withdrawal bleeding occurred, a responsive endometrium and an anatomically intact
genital tract could be assumed. After GnRH became available it was initially thought that the
response of LH and FSH to a bolus injection of GnRH would allow differentiation between
hypothalamic and pituitary insufficiency, but this proved soon to be a fallacy.
The above-mentioned diagnostic flow chart was the basis for deciding whether induction
of ovulation was worthwhile and by what means it should be done. In group II, i.e. patients
with a functional hypothalamic-pituitary-ovarian axis, clomiphene citrate was – and still is
– the agent of choice. Gonadotropin therapy was to be reserved for patients in Group I and
those of Group II who failed to respond to clomiphene citrate. Although GnRH was already
available for ovulation induction, the first trials of ovulation induction with GnRH were not
very successful; it took the work of Knobil and his group in the late 1970s to understand the
mandatory pulsatile character of GnRH administration. Although it was well-known that
galactorrhoea is associated with ovulatory dysfunction it was only in the mid-seventies of
the previous century that prolactin could be determined and the first dopaminergic
prolactin-lowering drugs became available for clinical use in the early 1980s.
Taking into account these new developments and therapeutic possibilities, the WHO
classification has been refined, but it still maintained the classification based on basal
oestrogen and gonadotropin level while at the same time acknowledging that anovulation
should be treated by the most appropriate and physiological way, i.e. anovulation due to
hyperprolactinemia should, in the first place, be treated with prolactin-lowering drugs and
Group I patients preferably should be treated by pulsatile GnRH treatment [4,5].

3. Scientific evidence
When looking back at the publication of Insler et al. [2], it is clear that this paper would
not have been accepted in later days by any self-respecting journal, not only because the
6 M. Dhont / International Congress Series 1279 (2005) 3–9

diagnostic tools used to classify the patients into three groups have become partially
obsolete but also because the paper lacks a number of essential data e.g. the methods used
to assess the presence or absence of ovulation, the infertility investigation, the exact
treatment schedule, the starting dose of HMG, how the treatment was monitored and the
outcome of treatment with gonadotropins with respect to ovarian hyperstimulation and the
incidence of multiple pregnancies. Furthermore, there is a large overlap between the three
groups with respect to the duration of treatment and the number of ampules of HMG used,
raising doubts whether this classification is strictly in accordance with the underlying
etiopathology.
After browsing the 1993 manual of the WHO for the dStandardized investigation
and diagnosis of the infertile coupleT I failed to find any reference to the so-called
WHO classification of anovulatory states into the three categories, although a number
of papers refer to this manual as being the bibliographic source of this classification
[4]. Some authors even refer to a 2000 WHO Manual, which in fact is exclusively
dedicated to the male partner [6,7]. This indicates that the WHO annual is frequently
cited without the citing authors having made the effort to effectively read this Manual.
In the second part of the 1993 manual, female causes of infertility are classified into
22 categories, of which categories 3, 4 and 5 are respectively: amenorrhoea with
elevated FSH, amenorrhoea with adequate endogenous oestrogen and amenorrhoea
with low endogenous oestrogen. Three further categories related to ovulatory
dysfunction being mentioned are oligomenorrhoea, irregular menses and/or ovulation
and anovulation with regular cycles without any reference to the underlying hormonal
dysfunction.
Although most patients with low endogenous oestrogen levels will be reliably classified
into Group I (low gonadotropin), there will be some discrepancies due to the fluctuating
nature of ovarian activity and the unavoidable overlap between low and normal values of
gonadotropins and oestrogens. The result of the progesterone withdrawal test does not
necessarily correlate with a single determination of oestradiol, which reflects the current
follicular activity, because the test is dependent on the prevailing impact of the sum of all
oestrogens during several weeks preceding the test and the individual variable response of
the endometrium to oestrogen and progesteron. The hypothalamic dysfunction in Group I
patients may be variable and no data exist to indicate at what level of dysfunction a trial of
ovulation induction with clomiphene citrate, an inexpensive and safe treatment, is totally
futile.
Patients with hypergonadotropic amenorrhoea will invariably be classified as Group III
(high gonadotropins). From a therapeutic point of view, it does not matter whether the lack
of ovarian response to gonadotropins is due to premature depletion of follicles or any other
reason.
Most problematic is Group II, the so-called normogonadotropic, normo-oestrogenic
cases, which by far, constitute the largest group of patients. This group is a mixture of
different hormonal dysfunctions which can primarily originate from diverse glandular and
even extraglandular sources. The most notorious subgroup among them are patients with
the PCOS, which in itself is an amalgam of different pathophysiological mechanisms. It is
generally accepted, however, that all these mechanisms converge in the ovary, which in
many cases has a typical polycystic aspect, to eventuate in follicular arrest and
 M. Dhont / International Congress Series 1279 (2005) 3–9 7

anovulation. This subgroup should be distinguished from normogonadotrophic patients

where anovulation is due to a primarily hypothalamic dysfunction.

4. Discussion
There are a few problems with the WHO classification of anovulatory states. The most
trivial but practically important one is that the numerical denomination does not
communicate anything about the underlying aetiology. For this reason, it is seldom if
ever used in clinical practice. Given the vast array of pathophysiological mechanisms
underlying anovulation, it also cannot satisfy the inquiring minds of students and
thoughtful clinicians. In fact, the level of gonadotropins and oestrogens is only a peripheral
reflection of what is going wrong within the principal actors involved in the regulation of
the menstrual cycle.
A further problem is that the diagnostic procedures advocated are no longer up to the
modern standards of investigation and the new insights in the physiopathology of
anovulation. For example, the role of transvaginal ultrasound in the evaluation of the
ovarian function and the endometrial development is not included. Furthermore, the
therapeutic flow chart that follows from it does not take into account the complex variety
of etiologies of anovulation, particularly concerning Group II. Although, as advocated in
the WHO Manual, the primary treatment of choice is clomiphene citrate in ascending
doses depending on the response, it gives no guidance to ancillary treatment options such
as weight loss in obese patients or insulin sensitizers. Furthermore, it does not give
guidance on the treatment of clomiphene resistant cases.
For all these reasons, it would be useful to devise a classification that refers to the
etiology of anovulation and at the same time gives a clue to the most appropriate therapy
(Table 2). Group I can be categorized as dhypothalamic dysfunctionT, characterised either
by a hypogonadotropic and consequently hypo-oestrogenic state or a normogonadotropic
state. In the former case, anovulation is due to a severely reduced output of GnRH and
treatment with pulsatile GnRH is the most logical therapeutic approach, unless there is a

Table 2
Revised classification of infertile women with anovulation
Main groups Subdivision Treatment
1. Hypothalamic 1.a Clomiphene-resistant Pulsatile GnRH
dysfunction (hypogonadotropic, hypo-oestrogenic)
1.b Clomiphene-responsive Gonadotropins
(normogonadotropic anovulation) Clomiphene
2. Ovarian dysfunction 2.a Lean patients Clomiphene
(PCOS) 2.b Obese patients Weight reduction
Metformin
Clomiphene
2.c Clomiphene-resistant patients Metformin+clomiphene
Ovarian drilling
HMG
3. Hyperprolactinemia Cabergolin
4. Ovarian failure Hormonal replacement therapy
8 M. Dhont / International Congress Series 1279 (2005) 3–9

rare primary pituitary problem. In normogonadotropic cases, anovulation is the result of a

cycle initiation defect, which in most cases can be resolved by clomiphene citrate. For
practical purposes, this group could also be subdivided in clomiphene responsive and
clomiphene unresponsive cases. In the latter case, the treatment of choice is pulsatile
GnRH administration. Ovulation induction with gonadotropins in these cases is only
second choice when the treatment with pulsatile GnRH or clomiphene citrate fails for
whatever reason.
Group II can simply be called PCO-syndrome (PCOS) or ovarian dysfunction. At an
expert meeting in 2003 in Rotterdam it was stated that PCO is a syndrome of ovarian
dysfunction along with the cardinal features of hyperandrogenism and polycystic ovary
morphology [7]. Although specific criteria for the diagnosis of PCOS remain elusive, it
was recommended that PCOS be defined when at least two of the following three features
were present, after exclusion of other etiologies: (i) oligo- or anovulation, (ii) clinical and/
or biochemical hyperandrogenism or (iii) polycystic ovaries. Its clinical manifestations
may include: menstrual irregularities, signs of androgen excess and obesity. The latter is an
adverse prognostic factor in the outcome of ovulation induction. Higher doses of
clomiphene citrate [8] and gonadotropins are required in obese patients [6]. Hyper-
insulinemia has been documented to occur in 50–100% of obese PCOS patients [9].
Because insulin resistance is frequently associated with PCOS, particularly in obese
women, it makes sense to further divide this group into obese and non-obese patients. In
the latter case, weight reduction and/or the use of insulin sensitizers are a mandatory
adjunct in ovulation induction [10,11].
Much research has been done, mainly by Dutch investigators, to delineate other
prognostic factors concerning both successful ovulation induction and pregnancy as the
final endpoint (reviewed by Laven et al., 2002 [12]), but it is questionable whether all
these prognostic factors should be incorporated to arrive at a more extended prognosis-
and treatment-oriented classification of PCOS patients.
Group III represents patients in whom anovulation is due to hyperprolactinemia and
should be a category apart because both the etiology and the treatment are specific and
Group IV represents the patients with ovarian failure.

5. Conclusion
The WHO classification of anovulatory states needs to be updated taking into account
the recent insights into the pathophysiology of anovulation and the modern methods of
diagnosis and treatment. The numerical classification should be replaced by straight
diagnostic categories related to the type and level of endocrine dysfunction. Particularly,
the WHO Group II should be reshuffled and should be reserved exclusively for PCOS
patients, which can be further subdivided into lean and obese patients and according to
their responsiveness to clomiphene citrate.

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