Hum. Reprod.-2006-Arrais-327-37

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Human Reproduction Vol.21, No.2 pp. 327337, 2006 doi:10.1093/humrep/dei3

Advance Access publication October 20, 2005.

The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. 32For Permissions, please email: [email protected]

The hypothalamuspituitaryovary axis and type 1 diabetes

mellitus: a mini review

R.F.Arrais

1,3

and S.A.Dib

2

1Children and Adolescent Endocrinology Unit, Department of Pediatrics, Federal University of Rio Grande do Norte, 59010-180, Natal

RN and 2Division of Endocrinology, Federal University of So Paulo, 04039-002, So Paulo, SP, Brazil

3To whom correspondence should be addressed: Departamento de Pediatria, Universidade Federal do Rio Grande do Norte UFRN, A

General Cordeiro de Farias, s/n, Petrpolis, 59010-180, Natal, RN, Brasil. E-mail: [email protected]

A high prevalence of menstrual cycle and fertility disturbances has long been associated with diabetes mellitus. How

ever, rationalization of the intrinsic mechanisms of these alterations is controversial and even contradictory. Th

review considers (i) the relationship between diabetes mellitus, especially type 1 diabetes mellitus (T1DM), and th

hypothalamuspituitaryovary (HPO) axis, (ii) the state of our knowledge concerning neuroendocrine control and i

relationship with dopaminergic and opioid tonus, and (iii) the influence of the hypothalamuspituitaryadrenal ax

on ovarian function. Functional disturbances that occur as a consequence of diabetes are also discussed, but som

T1DM-related diseases of autoimmune origin, such as oophoritis, are not further analysed. Although there are clea

indications of a relationship between menstrual and fertility alterations and glycaemic control, in many instances th

improvement of the latter is not sufficient to reverse such alterations. It appears that the oligoamenorrhoea an

amenorrhoea associated with T1DM is mainly of hypothalamic origin (i.e. failure of the GnRH pulse generator) an

may be reversible. The importance of the evaluation of the HPO axis in T1DM women with menstrual irregularitie

even in the presence of adequate metabolic control, is emphasized.

Key words: Diabetes/fertility/hyperandrogenism/menarche/menstrual dysfunction

Introduction

Systematic studies of the metabolic effects of type 1 diabetes

mellitus (T1DM) and type 2 diabetes mellitus (T2DM) on the

hypothalamuspituitaryovary (HPO) axis have revealed a

relationship between these diseases and menstrual distur-

bances, such as delayed menarche, alterations in the menstrual

rhythm (including primary and secondary amenorrhoea) and

potential consequences on fertility and fecundity.

Currently, through consideration of their aetiology and the

natural history of their development, it is accepted that T1DM

and T2DM are two distinct diseases. It is convenient, therefore,

to consider their effects on the HPO axis separately. Typically,

T1DM patients present some dysfunction in this axis at the age

of menarche (Adcocket al., 1994; Yeshaya et al., 1995), and

this is most pronounced when diabetes occurs before or at thepre-pubertal stage. The symptoms associated with T1DM

include accentuated delay of menarche and menstrual cycle

irregularities, i.e. amenorrhoea, oligomenorrhoea and poly-

menorrhoea (Yeshaya et al., 1995; Strotmeyer et al., 2003), as

well as precocious menopause and lower fertility (Yeshaya

et al., 1995, Dorman et al., 2001; Durando et al., 2003).

With respect to T2DM, correlations between the disease and

fertility, the age of onset of menopause and alterations in the

length of the menstrual cycle have been reported (Durando et al.,

2003). Variations in insulin sensitivity, which are normal

observed during the menstrual cycle, are typically exacerbated

patients with menstrual irregularities. These abnormalities mbe considered as a possible indicator for predicting the risk

glucose intolerance or of the development of T2DM (Pulido an

Salazar, 1999; Cooper et al., 2000; Solomon et al., 2001) with

the general population and especially in high-risk groups such

the Pima Indian women of Arizona (Roumain et al., 1998).

The present review focuses primarily on the alteratio

observed in the HPO axis of T1DM patients.

General principles of the function of the HPO axis

The hypothalamus plays a central role in the hormonal reg

lation of the female reproductive system. The sequence events corresponding to the menstrual cycle is induced by t

action of hormones released by the hypothalamuspituita

system on the ovarian follicle (Carr, 1998). The main regul

tory factor of reproductive function is GnRH, a decapeptid

secreted by the ventral medial nucleus of the hypothalamu

Production and further release of GnRH to the portal pituita

system are induced and controlled through stimuli receiv

from other regions of the brain via mediators of differe

origins.


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R.F.Arrais and S.A.Dib

328

Amino acids

Glutamate and -aminobutyric acid (GABA) are considered,with other neurotransmitters, to be important synaptic regula-

tors, exerting their functions through secretion by hypotha-

lamic nuclei on post-synaptic specific receptors, leading to

stimulation (glutamate) or inhibition (GABA) of GnRH neu-

rons (Reichlin, 1998).

Biogenic aminesMonoaminergic substances acting on the hypothalamic region,

such as dopamine and serotonin, are inhibitors of GnRH

release, while epinephrine and norepinephrine are inducers of

release. It is important to note, however, the relative unspecifi-

city of action of these substances, depending on the region con-

sidered, receptor characteristics and the influence of other

substances. Dopamine, for instance, has both and adrener-gic stimulation effects, and is converted to norepinephrine in the

hypothalamus. Dopamine and norepinephrine alter serotonin

secretion, which adds to the complexity of interpretation of

their actions on the HPO axis. The regulation of most hypotha-

lamic hormones and peptides is modulated by catecholamines

(a subgroup of amines that include dopamine and norepine-phrine). Release of GnRH is stimulated by -adrenergic sub-stances (e.g. ephedrine) and blocked by -blockers (e.g.phentolamine), knowledge that provides important tools for

experimental and therapeutic purposes (Reichlin, 1998).

Hormones

Prolactin has several effects on gonadotrophin secretion, mainly

inhibiting LH and FSH secretion at the pituitary level. Estradiol

has a diphasic effect on the mature pituitary and on hypotha-

lamic GnRH neurons, firstly inhibiting and secondly stimulating

its release. LH and FSH exert negative short loop feedback con-

trol of GnRH secretion and negative ultrashort loop feedbackcontrol of its own secretion (autocrine feedback). Progesterone

also has inhibitory direct effects on GnRH neurons. Inhibin, an

inhibitory regulator produced by the gonads, and activin, a spe-

cific FSH releaser, with follistatin (which inhibits the binding of

activin to its receptor) are major regulators of FSH action in

women (Reichlin, 1998; Rosenfield, 2002).

Opioid system

Endogenous opium-like peptides, or endorphins, comprise sev-

eral substances (met-enkephalin, leu-enkephalin, melanocortin,

-endorphin) derived from pro-opiomelanocortin (POMC; aprecursor); they inhibit the release of GnRH. Antagonistic

action of naloxone usually increases LH and FSH secretion.There is strong evidence that gonadotrophin secretion is regu-

lated by interaction between dopamine and endogenous opio-

ids, although it is not clear if this regulation is carried out

directly or is mediated via the dopaminergic system (Djursing,

1987; Reichlin, 1998).

Peptides

This class of organic substances comprises most of the pro-

tein compounds with hormonal activity at the hypothalamic

and pituitary level. It includes corticotrophin-releasing hor-

mone (CRH), thyrotropin-releasing hormone (TRH), thyroid-

stimulating hormone (TSH), vasopressin, oxytocin, somato-

statin, neuropeptide Y, melanocortin, growth hormone-releasing

hormone growth hormone-releasing hormone (GHRH) and

GnRH itself, among about 50 neuropeptides already

described and linked to specific neuronal tracts, which exert a

wide range of homeostatic and metabolic functions in the

HPO axis and other areas of the central nervous system

(Reichlin, 1998).

Fernandez-Fernandez et al. (2005) have recently observed in

rats a range of effects of gastrointestinal peptide hormones

(such as PYY, which acts through the neuropeptide Y central

receptors Y1 to Y5), ranging from stimulation, inhibition and

apparent modulation of LH and GnRH responses depending in

part ifin vivo or in vitro experiments are considered. This sug-

gests that there is a complex network involving the local hor-

monal milieu and interaction with other factors, such as leptin,

produced by adipose tissue. Vasoactive intestinal peptide

seems very important during normal maturation of the HPO

axis in rats (Kriegsfeld et al., 2000; Lebrethon et al., 2000) and

pigs (Bogacka et al., 2002). These studies reinforce the ideathat gastrointestinal peptides, mainly by influencing neuropep-

tide Y receptors associated with the action of leptin, establishes

the hormonal basis for the interaction between energy balance

control and reproductive function in mammals.

GnRH, LH/FSH and estrogen physiology

GnRH regulates the synthesis, storage and mobilization of the

gonadotrophins as well as their acute release (Carr, 1998). The

mechanism of action of GnRH involves the binding of the hor-

mone to a transmembrane receptor, which leads to an increase in

cAMP and the subsequent elevation of cytoplasmic Ca2+ or acti-

vation of protein kinase C (Conn, 1986; Conn and Crowley,

1991). GnRH, which has a half life time of 24 min, reaches thepituitary very rapidly and induces the release of LH and FSH.

Normally, GnRH is released in pulse mode at regular intervals of

1 h in order to induce the physiological release of FSH and LH in

a pulsating manner. The release of GnRH in continuous mode, or

in pulses at intervals longer or shorter than 1 h, does not produce

normal pulses of LH and FSH (Carr, 1998). However, in women

with a single deficiency of GnRH, pulsed treatment with GnRH

was efficient in inducing ovulation and fertility (Knobil, 1980).

There are three distinct patterns of secretion of the gonado-

trophins: (i) monthly, characterized by low-level fluctuations

in LH and FSH secretion that occur every 30 days during the

normal menstrual cycle; (ii) daily, characterized by intermittent

LH and FSH release, with larger bursts during sleep. Differ-

ences between wake and sleep secretion are larger in girls at

the beginning of puberty, with low levels during the day,

and increased, progressively higher bursts during sleep. (iii)

hourly, characterized by the pulsed release of LH and FSH

(Leyedecker et al., 1980; Reichlin, 1998).

FSH and LH are secreted in a coordinated manner in order

to promote the development of the ovarian follicle, ovulation

and maintenance of the corpus luteum. The release of FSH

and LH is either positively or negatively modulated by estrogen


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HPO axis and type 1 diabe

32

and progesterone, depending on the concentration and period

of exposure of the pituitary to these steroids (Fink, 1988).

There is a negative feedback between the secretion of estrogens

and the release of gonadotrophins from the hypothalamus

(GnRH) and the pituitary (FSH, LH), and this can be particularly

noticeable when there is an increase in the secretion of FSH

and LH, as in menopausal women and castrated men. The

inhibition of FSH and LH may occur when estrogen levels

are low, but is more evident when the levels are high. A rapid

increase in the level of estrogens can exert a positive effect

on the secretion of gonadotrophins, and this is of crucial

importance to the production of the LH peak required for the

induction of ovulation. Two aspects are important in this

mechanism, namely, an estrogen concentration higher than

700 pmol/l (200 pg/ml) and a constant elevated level of estra-

diol for a period of 4850 h. Progesterone at high concentra-

tions inhibits the release of both FSH and LH (Carr, 1998)

and is also responsible for the FSH peak. At low levels, pro-

gesterone stimulates the secretion of LH, but only after

lengthy exposure of the pituitary to estrogen.

Together with steroids, gonadal proteins modulate the

release of FSH; these proteins comprise activin (which stimu-lates biosynthesis and release of FSH) and inhibin and follista-

tin (which specifically suppress the release of FSH; Ying,

1988). The secretion of activin by the granulosa cells of devel-

oping follicles increases the release of FSH (Carr, 1998).

Since the mid 1970s, the HPO axis has been evaluated using

the GnRH stimulation test, which assesses indirectly the

response of the pituitary gland to stimulation by exogenous

GnRH. This test permits identification of the causes of gonadal

failure, such as different types of amenorrhoea and hypogonad-

ism (Czygan et al., 1974; Donald and Espiner, 1974; Valcke

and Mahoudeau, 1974; Keller et al., 1975; Wierdis et al.,

1978). Research carried out in Italy involving patients present-

ing amenorrhoea and eumenorrhoea of diverse aetiologies,including diabetes, concluded that the GnRH stimulation test

helped with the differential diagnosis of the amenorrhoeas, as

well as with the evaluation of pituitary reserves (Wierdis et al.,

1978). Comparing the performance of the test described in dif-

ferent reports, however, presents some difficulty since the dose

of GnRH typically used to produce an acute stimulus varies

between 10 and 100 g.

Epidemiology of menstrual disturbances in patients with

type 1 diabetes mellitus

Since the 1950s it has been well recognized that diabetic

patients may suffer a delay in their sexual maturity and in theage of menarche, particularly when the onset of diabetes

occurred in the pre-pubertal period (Bergquist, 1954; Worm,

1955; Kjaer et al., 1992). Pre-pubertal diabetic children present

normal levels of basal gonadotrophins but reduced responses to

GnRH, indicating that they probably have limited capacity to

maintain an adequate pituitary reserve (Cicognani et al., 1978).

In girls presenting the first symptoms of diabetes after the age

of 11 (i.e. near to the expected age of menarche), the onset of

menarche was much later than in non-diabetic girls, suggesting

a disorder of the HPO axis (Schriock et al., 1984). Further-

more, diabetes is also associated with the premature cessatio

of menstrual cycles, thus leading to a shortening of the ferti

period of diabetic patients by up to 17% (Bergquist, 195

Dorman et al., 2001; Durando et al., 2003). The basic causes

this curtailment of reproductive life may be explained b

disorders of the HPO axis, generated by metabolic defects

by adrenal insufficiency, defective opioid modulation of t

hypothalamus and autoimmune factors (Snajderov et al., 1999

There is evidence of a positive correlation between the co

trol of glycaemia and the menstrual cycle in diabetic wome

Irregularities, most frequently amenorrhoea and oligomeno

rhoea (Djursing et al., 1981), are expected only in the fir

2 years following menarche in non-diabetic adolescen

(Rosenfield, 2002), but are present in about 2030% of di

betic patients (Bergquist, 1954; Worm, 1955; Karimova, 198

Kjaer et al., 1992; Adcocket al., 1994; Yeshaya et al., 199

Schroeder et al., 2000; Durando et al., 2003; Strotmeyer et a

2003). The onset of diabetes appears to be an important preci

itating factor for the initiation of menstrual disorders, an ass

ciation that can be clearly observed in at least 50% of the

patients (Djursing et al., 1982). The majority of amenorrhoe

diabetic patients present functional amenorrhoea with no evience of abnormalities in the HPO axis (Worm, 1955; Djursin

et al., 1982). Whilst amenorrhoea in non-diabetic patients

provoked by loss of weight (50% of cases) and other unknow

factors (Djursing, 1987), in diabetic patients it is triggered b

the disease itself (40% of cases) regardless of the cause (i

primary, functional or non-specific). One of the specific caus

of amenorrhoea may be related to the incidence of autoimmu

disorders that exist in T1DM patients. Snajderov et al. (199

reported a higher prevalence (67.9%) of autoantibodies direct

against at least one of the ovarian tissues analysed (ooplasm

pellucid zone, granulosa membrane, internal theca and lute

cells) of juvenile and adolescent diabetic females, when com

pared with non-diabetic adolescents and young women (4.8%Whilst a positive reaction for autoantibodies in the estroge

producing regions (granulosa and lutein cells) was detected

the same proportions of diabetic patients with and witho

menstrual irregularities, autoimmune thyroiditis was found in

much larger fraction (80%) of patients with menstrual irreg

larities.

A study conducted in Russia (Karimova, 1983) involvin

157 diabetic women of fertile age (59% of whom had been su

fering from the disease for up to 5 years), showed that 73.6

presented obstetric problems and 33% suffered from distu

bances of the menstrual cycle. This study indicated a correl

tion between ovarian dysfunction and severe diabetes.

Another study (Burkart et al., 1989), involving 337 Germwomen with T1DM, concluded that the age of menarche w

inversely proportional to the age at which the disease emerge

In patients in whom the disease appeared before puberty, pa

ticularly between the ages of 3 and 8 years, menarche occurr

0.82 years later than in patients in whom diabetes emerge

after menarche and 0.41.3 years later than in the health

population. Furthermore, women suffering from diabetes fro

an early age presented a more pronounced form of the diseas

Primary amenorrhoea appeared in 3.6% of women who ha

been suffering from diabetes prior to puberty, i.e. younger th


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330

9 years old, but in only 1.5% of normal women and those in

whom the disease emerged after the age of 9 years. Some 14%

of the pre-pubertal diabetic group presented oligomenorrhoea

and 7% secondary amenorrhoea, whilst the post-pubertal dia-

betic group showed only secondary amenorrhoea (12%). Irreg-

ularities in the menstrual cycle occurred more frequently at the

emergence of diabetes and tended to normalize during its evo-

lution. Amongst patients who were 35 years old and above,

approximately 70.5% had spontaneous pregnancies and 2.1%

were sterile; these percentages were not significantly different

from those of the normal population.

A similar study in Denmark (Kjaer et al., 1992) involving

245 diabetic patients and 253 normal women reported that

menarche in the pre-pubertal diabetic group occurred 1 year

later than in the normal group. In addition, 21.6% of the dia-

betic patients presented menstrual disturbances compared with

only 10.8% (P < 0.005) of the normal population; thus, 4.9% of

the diabetic group presented primary amenorrhoea compared

with 1.2% of the normal group (P < 0.05), 8.2% presented sec-

ondary amenorrhoea (cf. normal value of 2.8%; P < 0.01),

10.6% presented oligomenorrhoea (cf. normal value of 4.8%;

P


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33

fasting state and the LH peak, suggesting an influence of

glucose metabolism on pituitary function, even though this

defective metabolism could not be the sole cause of menstrual

abnormalities.

There is evidence that hyperglycaemia interferes with basal

levels of gonadotrophins and with levels following stimulation

with either GnRH alone or with GnRH, TRH and arginine

simultaneously (Vierhapper et al., 1981). These authors stud-

ied six T1DM patients under euglycaemic or hyperglycaemic

clamp and observed that in both conditions there was no differ-

ence with respect to the FSH, LH, TSH or prolactin responses,

even in the absence of insulin infusion. However, the response

to growth hormone (GH) was suppressed during the hypergly-

caemic clamp, and this effect was attributed to the action of

arginine on the hypothalamus, suggesting that the modulating

influence of hyperglycaemia on the secretion of GH occurs

mainly at the hypothalamus level and not at the pituitary level.

In diabetic patients who have not been appropriately treated,

the metabolic stress produced by ketoacidosis activates an

adrenal catecholaminergic response, since plasma epinephrine

and norepinephrine are elevated in such individuals (Christensen,

1970). Although dopamine (a precursor of epinephrine andnorepinephrine) does not normally cross the haematic

encephalic barrier, permeability to this neurotransmitter may

be altered in diabetic patients (Lorenzi et al., 1980). Dopamine

inhibits the secretion of LH (Hagen et al., 1984) and causes a

consequent increase in the levels of other catecholamines in the

central and peripheral nervous systems that in turn produces a

metabolic disorder in non-treated patients, leading to the

abnormal secretion of gonadotrophins (Djursing, 1987).

Normal levels of plasma prolactin (Naejie et al., 1979;

Bratush-Marrain et al., 1980), as well as moderately elevated

levels (Hansen and Torjesen, 1977), have been reported in

ketoacidotic diabetic women. In hyperprolactinaemic patients,

normal gonadal function may be suppressed because of the dir-ect inhibitory effect of prolactin on ovarian steroidogenesis

(Andersen, 1984) together with inadequate release of GnRH

caused by defective feedback between estrogens and gonado-

trophins (Djursing et al., 1981) or by a short-loop positive

feedback of prolactin on the liberation of dopamine (Djursing

et al., 1981. In patients suffering from amenorrhoea, an

increase in prolactin and FSH following stimulation with meto-

clopramide (MTC), a dopaminergic inhibitor, was observed

(Djursing et al., 1985a, b) but there were no alterations in LH,

suggesting an enhancement in dopaminergic activity in these

patients.

Together with functional defects in the hypothalamus and

the pituitary gland, disturbances in endorphin (endogenous opi-oid) tonus, leading directly or indirectly to an increase in

dopaminergic tonus and a decrease in the LH pulse, have been

identified as possible causes of menstrual dysfunction (Griffin

et al., 1994; Morley, 1998).

Diabetes and ovarian function

Studies in animal models

Diabetic experimental animals exhibited a decrease in proges-

terone production (Tesone et al., 1983) and normal or diminished

production of estrogens (Kirchicket al., 1978; Katayama et a

1984). The alteration in steroidogenesis could be related eith

to the reduction in GnRH and secretion of gonadotrophin

(Johnson and Sidman, 1979) or to a reduction in the affinity

number of gonadotrophin receptors in the ovarian cel

(Tesone et al., 1983).

Studies in humans

Ovarian function may be impaired with respect to steroidogeesis as a direct or indirect consequence of the defective HP

axis. The abnormal secretion of steroids was demonstrated b

Djursing et al. (1985b) in a study including diabetic and no

diabetic women suffering from amenorrhoea or without ame

orrhoea. The diabetic amenorrhoeic group showed low leve

of steroid hormone-binding globulin (SHBG), estradiol, test

sterone and other androgenic and estrogenic steroids whe

compared with both the diabetic and the non-diabetic eumeno

rhoeic groups. The levels of4-androstenedione and testosteone were higher in the diabetic eumenorrhoeic group compar

with their non-diabetic counterparts. It was concluded that th

menstrual abnormalities could be a consequence of the su

pression of the HPO axis, since the slight hypoandrogenisrevealed by the diabetic amenorrhoeic patients could n

explain the relationship between amenorrhoea and diabete

The low estrogenic levels in diabetic amenorrhoeic wom

were attributed to ovarian suppression, whilst the high levels

androgens in diabetic eumenorrhoeic women were considere

to be of ovarian origin. Gluud et al. (1982) also detected

decrease in testosterone and androstenedione levels in s

ketotic diabetic women of fertile age, suggesting suppressio

of the hypothalamuspituitary system.

Adcocket al. (1994) reported that diabetic women sufferin

from menstrual irregularities also presented impaired met

bolic control, lower levels of SHBG and higher LH/FSH ratio

Furthermore, 77% of these women presented signs of polcystic ovary syndrome.

The evidence concerning steroidogenic dysfunction among

T1DM women suffering from amenorrhoea is further corrob

rated by measurements of the estrogen/progesterone rati

Zumoffet al. (1990) demonstrated that in T1DM patients th

ratio was two-fold higher during the follicular phase than th

presented by non-diabetic women. It was suggested that the

patients were at risk of developing atherogenic and cardiova

cular problems, since the elevated estrogen/progesterone rat

was due partly to an increase in serum estradiol levels and al

to a decrease in progesterone, which is a protective fact

against coronary artery disease.

Figure 1 summarizes the physiopathology of diabetes wi

respect to the HPO axis, and shows the most important featur

associated with the relationship between diabetic hyperglyca

mia and metabolic and hormonal dysfunction, leading to t

impairment of gonadal function in women with T1DM.

Evaluation of the HPO axis in patients with type 1 diabete

mellitus and regular menstrual cycles

Alterations in HPO function in T1DM patients with norm

menstrual cycles are presumably quite minor since ovulation


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332

preserved (Bergquist, 1954; Worm, 1955). However, even

these small alterations in the HPO axis, although not generat-

ing menstrual disturbances, provide an insight into menstrual

dysfunction in diabetic patients (Djursing, 1987). For instance,

it is known that diabetic women (particularly of perimenopau-

sal age) present slightly reduced levels of prolactin, consistent

with a small increase in dopaminergic tonus, together with a

diminished response of the lactotrophs to TRH stimulation.The fact that, following administration of MTC, the prolactin

levels in diabetic women with normal menstrual cycles are the

same as those found in non-diabetic women leads to the con-

clusion that the lower basal levels and the reduced secretion of

prolactin found in the former group are a consequence of the

effect of a slight increase in dopaminergic activity on the lac-

totrophs (Djursing, 1987). With respect to the gonadotrophins,

diabetic patients with normal menstrual cycles present normal

levels in the follicular phase (Distiller et al., 1975), and normal

pulses (Djursing et al., 1985a), which are not affected by the

dopaminergic blockade induced by MTC. The logical conclu-

sion is that the dopaminergic activity is normal or that the

GnRH-producing neurons are insensitive to changes indopaminergic activity (Djursing, 1987).

In diabetic patients with regular menstrual cycles, the fluctu-

ation of plasma catecholamines is modest, showing an increase

in peripheral plasma dopamine and a decrease in conjugated

dopamine. This relative increase in the ratio between active

dopamine and conjugated dopamine could exert an effect on

prolactin occasioned by an increase in permeability of the

haematicencephalic barrier (Dursing, 1987). Such an increase

in permeability was suggested by Godrum et al. (1995) follow-

ing studies using low doses and continuous infusion of

dopamine in eumenorrhoeic diabetic patients and in normal

women. In the latter group, treatment with dopamine had no

effect on the average basal LH level, the amplitude of LH

pulses and the frequency of pulses, but in the former group the

basal levels of LH and the amplitude of the pulses were

reduced by dopamine, although the frequency of the pulses

remained normal. Alterations in the values of these parameters

indicated that diabetic patients are more sensitive to minor aug-mentation of peripheral dopamine levels.

Dopamine also influences the pituitary secretion of TSH and

GH. In normal women, dopamine acts as a physiological inhib-

itor of TSH secretion at both the hypothalamic and the pituitary

level. However, in eumenorrhoeic diabetic women, administra-

tion of the dopaminergic inhibitor MTC produced a diminished

response of TSH to TRH compared with that found in normal

women. The positive correlation between basal and MTC-

stimulated TSH levels suggests that the diminished response of

TSH is due to down-regulation of the number or affinity of the

dopamine receptors in the thyrotrophs caused by the increased

dopaminergic activity (Djursing et al., 1984). The positive cor-

relation between basal and MTC-stimulated TSH levels alsosuggests that the discreet alteration in dopaminergic activity

must be responsible for the lower levels of TSH presented by

eumenorrhoeic diabetic women.

In diabetic patients, the secretion of GH is stimulated by

dopamine, the highest levels being detected at the follicular

phase of the cycle. MTC blockage, however, does not produce

a significant increase in GH levels, the reason for which may

be that dopamine influences somatostatin and GHRH. Two

hypotheses can be deduced from this situation: (i) In each of

the systems there are different affinities that may influence the

Figure 1. Schematic representation of hypothalamuspituitaryovary (HPO) axis in normal and diabetic women. The inhibitory effects of dia-

betic hyperglycaemia on the HPO axis are represented through the inter-relationships of metabolic dysfunction in both opioid and dopaminergicsystems, and the hypothalamuspituitaryadrenal axis. The plausible inhibitory effect of autoantibodies on the ovarian function is also repre-sented. H = hypothalamus; P = pituitary; O = ovary; BBB = bloodbrain barrier; DA = dopamine; PRL = prolactin; DKA = diabetic ketoacidosis.Arrows: continuous lines, stimulation; dashed lines, inhibition; interspaced lines, modulation.

H

P

O

H

P

O

Normal Women Diabetic Women

GnRH

Stimulation:Epinephrine

Norepinephrine

BBB permeability

Inhibition:

Dopamine

Serotonin

Modulation:

Opium-like

peptides

LH

E2

FSH

Chronic /Acute

Hyperglicaemia

DKAStress

PRL

Opioid

Activity

LH FSH

DA

Adrenal

Response

Androgens

Normal BBB

Auto-immune

Oophoritis

GnRH

DA


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33

effect of MTC on the release of GH; and (ii) MTC has little

influence on either system (Djursing et al., 1984). The conclu-

sion is that the augmentation of dopaminergic activity interferes

with the modulation of both TSH and GH (Djursing, 1987).

The abnormalities found in eumenorrhoeic diabetic women

can also be explained by a disruption of opioid modulation that

progresses with the disease. Coiro et al. (1991) analysed 29

eumenorrhoeic diabetic women, one group of whom had been

suffering from the disease for between 3 and 9 years and the

other for 1020 years. The two groups were subjected to

GnRH or naloxone (an opioid antagonist) stimulation: the LH

response in the first group was similar to that of normal women

but the second group presented a reduced LH response, indicat-

ing a negative correlation between the duration of the disease

and the LH peak.

Reports concerning the levels of sex steroids in diabetic

patients are not completely consistent. Diabetic patients with no

menstrual disturbances were found to present normal levels of

estrogens and elevated androstenedione and testosterone

(Djursing et al., 1985b), but normal levels of testosterone in such

patients have also been reported (Gluud et al., 1982). This dis-

crepancy may be due to the different criteria used for the selectionof patients in these studies (Djursing, 1987). Androstenedione is

converted to testosterone and, since a direct correlation between

androstenedione and testosterone in T1DM patients with normal

cycles has been found, the increased testosterone levels observed

may be a consequence of increased secretion of androstenedione

(Djursing et al., 1985b). Despite the high levels of androstenedi-

one and total testosterone recorded exclusively in diabetic

patients with normal cycles, there was no increase in free testo-

sterone or in dihydrotestosterone, the formation of which

depends on 5-reductase activity. These results explain whythere were no signs of hyperandrogenism or menstrual dysfunc-

tion in these patients despite their high levels of total androgens

(Djursing et al., 1985b). Furthermore, the levels of SHBG wereincreased in such patients; whilst synthesis of this protein is stim-

ulated by estrogens and thyroid hormone, it is inhibited by GH

and androgens and by reduced sensitivity of the target organs

(Djursing et al., 1985b; Djursing, 1987).

Evaluation of the HPO and hypothalamuspituitary

adrenal axes in patients with type 1 diabetes mellitus

and functional amenorrhoea

Normally, evaluation of the HPO axis in diabetic patients suf-

fering from functional amenorrhoea reveals hypofunction, with

disorders of the feedback mechanisms that appear to be inde-

pendent of the dose of insulin being used and of the age atdiagnosis of diabetes. In addition, these disorders are appar-

ently not coupled with the duration of treatment but are pre-

dominantly related to the dopaminergic inhibition that is often

associated with the dysfunction of opioid peptides, which act

as hypothalamic modulators (Djursing, 1987).

In amenorrhoeic diabetic women, basal FSH levels are low

even when basal estrogens are low, but the response of FSH to

GnRH stimulation remains normal. This suggests insufficient

secretion of gonadotrophins or a disturbance in the feedback

mechanism in such patients (Djursing et al., 1983, 1985b).

South et al. (1993) compared LH levels in eumenorrhoe

non-diabetic women and in women with T1DM who ha

unsatisfactory metabolic control and secondary amenorrhoe

Determination of LH was carried out over a period of 24 h fo

lowing GnRH stimulation, and the results showed that, com

pared with the control group, there was a reduction in t

number of LH peaks during the day in diabetic women, but th

the amplitudes and areas of the peaks were larger. This hype

response to GnRH suggested that secondary amenorrhoea

more connected to dopaminergic tonus (interference in t

generation of hypothalamic pulses) than to pituitary malfun

tion (deficient liberation of gonadotrophins).

Attempts to control the excess dopaminergic activity pr

sented by amenorrhoeic diabetic women through administr

tion of MTC resulted in a doubling of FSH levels (Hage

et al., 1983) but, in contrast to the situation for amenorrhoe

non-diabetic women, did not result in increases in estradi

and LH (Djursing et al., 1985a). This suggests a lack

response of the ovary to FSH, leading to disruption of the po

itive feedback mechanism for LH. The basal levels, bo

amplitude and pulse number, of LH are diminished in diabet

patients with menstrual disturbances and eumenorrhoea compared with non-diabetic patients (Djursing et al., 1985a). T

response to GnRH is also compromised and correlates pos

tively with the low levels of estrogens (Djursing et al. 1983

Since the sensitivity of the LH-producing gonadotrophs

GnRH is modulated by estrogens (Djursing et al., 1983) an

the capacity of the gonadotrophs to respond to estrogen

feedback is intact, the reduced capacity for the production

estrogen could be one of the reasons why amenorrhoeic di

betic women produce low levels of LH (Djursing et a

1985b). Alternatively, the insufficiency of LH could be cause

by depletion of GnRH occasioned by its inadequate release

reduction in the sensitivity of the gonadotrophs to GnRH,

the failure of the pituitary to secrete LH after an extendeperiod of GnRH deprivation.

Dopaminergic activity is probably elevated in amenorrhoe

non-diabetic women presenting an absence of LH response

the dopaminergic agonist bromocriptine (Djursing et al., 198

and a positive LH response to the dopaminergic antagoni

MTC (Hagen et al., 1983). The administration of MTC induc

a significant LH response in a larger proportion of ameno

rhoeic diabetic women compared with eumenorrhoeic diabet

and non-diabetic women (Djursing et al., 1985a), suggestin

greater dopaminergic suppression of LH secretion in the fir

group (Hagen et al., 1983). This mechanism could be mediat

by the increased GnRH that accumulates inside the neurons

the hypothalamus as a result of suppressed secretion (Djursin1987). Lifting the dopamine inhibition may result in increas

in GnRH and gonadotrophins.

The basal prolactin concentration is diminished in ameno

rhoeic diabetic women compared with eumenorrhoeic diabet

and non-diabetic women (Djursing et al., 1982). The inhib

tion of prolactin is mediated by the dopamine recepto

present in the lactotrophs; therefore the increase in dopami

ergic activity may be the principal cause of the low levels

prolactin found in amenorrhoeic and even in eumenorrhoe

diabetic women. In amenorrhoeic diabetic women the prolact


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334

response to the TRH test is normal (Djursing et al., 1983),

indicating that the integrity of the receptors for TRH in the

lactotrophs is preserved. However, the pool of available prolactin

in such patients is lower, as indicated by a reduced prolactin

response to MTC-mediated dopaminergic inhibition in com-

parison with that exhibited by eumenorrhoeic diabetic and

normal women (Djursing et al., 1985b). The reduction in the

available pool of prolactin following prolonged exposure to

excess dopaminergic activity may be a consequence of the

down-regulation of the TRH receptors or a decrease in their

number or activity. Since estrogens increase the release of

prolactin in normal women, the fact that the basal levels of

these steroids are diminished in amenorrhoeic diabetic women

may contribute to the low levels of prolactin found in these

patients (Djursing, 1987).

Although the peripheral levels of non-conjugated dopamine

are low and the ratio of free to conjugated dopamine is more

elevated in amenorrhoeic diabetic women, the levels of epine-

phrine and norepinephrine remain unaltered. There is no

evidence of a correlation, however, between the levels of

peripheral catecholamines and the secretion of the hypothala-

muspituitary hormones that are modulated by dopamine(Djursing, 1987).

The role of endogenous opioids

A review from Morley (1983) stressed the inhibitory effects

exerted by opioid compounds on the liberation of GnRH from

the hypothalamus. Endogenous opioids appear to have little

effect on the basal secretion of prolactin, unlike pharmacologi-

cal doses of opioid agonists that increase the secretion of prol-

actin, leading to hypogonadism and impotence in men

submitted to intrathecal opioid therapy for the cure of non-

tumoral chronic pain (Roberts et al., 2002). Whilst opioid

antagonists have no effect on the increase in MTC-inducedprolactin (Laurian et al., 1981), dopamine inhibits the increase

in gonadotrophins induced by opioid antagonists (Delitala

et al., 1980). Based on such evidence, it is believed that gona-

dotrophin secretion is regulated by an interaction between

dopamine and endogenous opioids, although it is not clear if

this regulation is carried out directly or is mediated via the

dopaminergic system (Djursing, 1987).

OHare et al. (1987) studied the response to the opioid

inhibitor naloxone in five hypogonadotrophic amenorrhoeic

women with T1DM whose disease had not been fully con-

trolled. Following successful intensification of the insulin

treatment, the levels of FSH and LH in all patients remained

unchanged and, furthermore, menstruation was not initiated.GnRH inhibition mediated by opioid compounds occurs in

some amenorrhoeic women (Sauder et al., 1984), suggesting

that the alterations in basal and GnRH-stimulated LH found in

these patients result, in part, from modification of the activity

of endogenous opioids. Corroborating evidence of alterations

in plasma opioid activity in diabetic humans has been provided

by several reports (Awoke et al., 1984; Caprio et al., 1991)

showing that diabetic patients respond well to opioid inhibition

therapy with naloxone, resulting in more efficient control of

hypoglycaemia. Such positive effects may be explained by the

improvement in cortisol and epinephrine release that had been

suppressed by endogenous opioid modulation in these patients

(Caprio et al., 1991).

Thyroid function

TSH levels are significantly lower in amenorrhoeic diabetic

women compared with eumenorrhoeic diabetic and non-

diabetic women. The plasma thyroid hormone levels are also

normal and there is no association with alterations in rT3(Djursing et al., 1982). This suggests that the low TSH levels

are caused by the reduced secretion of TSH rather than by

alterations in the binding capacity or peripheral metabolism of

the thyroid hormones. Dopamine inhibits the release of TSH at

the hypothalamuspituitary level and the TSH response to the

blockade of dopaminergic receptors by MTC is normal in

amenorrhoeic diabetic women. The enhancement in dopamine

activity in the TRH-releasing neurons and pituitary thyrotrophs

explains the low basal TSH and the normal TSH response fol-

lowing the use of MTC. Because dopamine inhibits the release

of TRH, treatment with MTC liberates the pool of this hor-

mone. However, the effect of high TRH is counterbalanced by

the inability of the pituitary to respond with the discharge ofTSH owing to the chronic inhibition of dopaminergic activity.

Basal GH is also increased in amenorrhoeic diabetic women

and, because there is a correlation between the secretion of GH

and dopaminergic tonus, the elevated basal GH levels suggest

that these patients are under the influence of high central

dopaminergic activity (Djursing, 1987).

The role of androgens and the hypothalamuspituitary

adrenal axis

Studies in animal models

Hyperactivation of the hypothalamuspituitaryadrenal (HPA)

axis was observed in diabetic rats, the stress responses ofwhich were defective and involved a diminution of pituitary

corticotroph sensitivity to CRH as well as a reduction in adrenal

cortex sensitivity to adrenocorticotrophic hormone (ACTH)

(Chan et al., 2002). Such hyperactivation could be partially

repaired by administration of insulin and normalization of pitu-

itaryadrenal function. Thus, hyperactivation of the HPA axis

may be seen as a consequence of an increase in central activity

or a decrease in the sensitivity of the negative feedback mecha-

nism of glucocorticoids.

Studies in humans

Increased levels of ovarian and adrenal androgens may be the

cause of amenorrhoea in women (Carr, 1998). However, stud-ies have demonstrated that amenorrhoeic diabetic women

present lower levels of estrogens, androgens and their precur-

sors compared with eumenorrhoeic diabetic women. Further-

more, amenorrhoeic diabetic women exhibit lower levels of

SHBG (Anderson, 1974; Djursing, 1987) and less dihydrotes-

tosterone and estradiol (both free and protein-bound) compared

with normal women (Djursing et al., 1985b). In fact, steroid

production in the ovaries is defective in amenorrhoeic diabetic

women, and this condition is due in part to inadequate gonado-

trophic stimulation, as confirmed by the inferior levels of basal


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33

and GnRH-stimulated LH found in these patients (Djursing

et al., 1983, 1985b).

Whilst the diurnal excretion of pregnanetriol was normal in

amenorrhoeic diabetic women (Djursing et al., 1982), the

levels of dehydroepiandrosterone sulphate were lower than in

eumenorrhoeic diabetic and normal women (Djursing et al.,

1985b). Some amenorrhoeic diabetic women presented a mod-

est increase in free cortisol excreted in the urine (Djursing

et al., 1982), probably because of increased production since

there was no renal impairment in these patients. None of the

group presented clinical signs of hypercortisolism. Glucocorti-

coid hyperactivity is generally accompanied by an increase in

estrogenic and androgenic activity, but this condition is not

normally observed in amenorrhoeic diabetic women. Typically

there is no correlation between changes in adrenal hormone

parameters and alterations of the gonadotrophic axis (Djursing

et al., 1985b), making adrenal hyperactivity an unlikely expla-

nation for the incidence of amenorrhoea amongst diabetic

women (Djursing, 1987). Virdis et al. (1997), following studies

on a group of oligomenorrhoeic adolescents with T1DM before

and after stimulation with an GnRH analogue (leuprolide), sug-

gested that adrenal hyperactivity may precede and cause partialgonadotrophic insufficiency, with progressive disarray of the

hypothalamic generator of GnRH pulses. Their conclusions

were based on the fact that a higher 17-hydroxyprogesterone

response was observed in this group than in eumenorrhoeic

diabetic and normal women.

The HPA axis was studied in both amenorrhoeic and eumen-

orrhoeic diabetic women (De Veo et al., 1999), and the results

showed that the former group had lower basal levels of LH,

FSH, prolactin, estradiol, androstenedione and 17-hydroxypro-

gesterone compared with the latter, as well as a diminished

ACTH response to the CRH test and a diminished prolactin

response to the MTC inhibition test. However, the prolactin

response to the CRH test and the 24 h cortisol evaluation test(notably between 0 and 10 a.m.) provided higher values for the

amenorrhoeic than for the eumenorrhoeic patients, indicating

hyperactivation of the HPA axis. This study emphasized the

importance of considering well-controlled amenorrhoeic dia-

betic patients as having functional amenorrhoea that requires

specific clinical treatment. Other studies support the role of the

HPA axis in the metabolic effects of diabetes, such as the

counter-regulation of hypoglycaemia and disturbances in the

response to stress.

Conclusions

For better evaluation of menstrual disturbances in diabeticpatients, mainly those presenting amenorrhoea and alterations

in the duration of the cycle, it seems worthwhile to include an

evaluation of the integrity of the HPO axis, as determined by

quantification of prolactin, adrenal hormones, estrogens and

androgens. Such data could be very valuable with respect to

patients in whom medication produces an improvement in

metabolic control but in whom normal menstrual cycles are not

re-established. It appears that, in such cases, menstrual distur-

bances are not related to any particular intensity of metabolic

disarray. Furthermore, interfering factors are numerous and the

relative influence of the lack of full metabolic control on th

generation of such disorders varies individually.

Unfortunately, the therapeutic approaches used to treat me

strual disturbances and to control diabetes are still restricte

The use of dopaminergic inhibitors, such as MTC, togeth

with erythromycin, cisapride and domperidone, is limited

cases of diabetic gastroparesis that do not respond to chang

in diet (Smith and Ferris, 2003).

Studies concerning the use of opioid inhibitors, such

naloxone and naltrexone, are limited to acute responses, gene

ally involving intravenous infusions to stimulate the intensi

of the opioid barrier (OHare et al., 1987). More recent studi

suggest the use of opioid inhibitors in regenerative processe

for example, a 4-week application of naltrexone in the trea

ment of cornea lesions in rats leads to more rapid recover

(Zagon et al., 2002). Moreover, Raingeard et al. (2004) treat

women with T1DM who presented nutritional psychiatric di

orders (bulimia and binge-eating) with naltrexone for 1 ye

and achieved satisfactory results.

Studies on critically ill patients maintained in an intensi

therapy unit revealed that the response of the hypothalamu

pituitary undergoes alteration in two distinct phases, acute anchronic, with detectable effects in all areas (somatotrophi

thyrotrophic, gonadotrophic and adrenocorticotrophic) (Van D

Berghe, 2002). The initial release of secretagogues (GHRH

TRH, GnRH and ACTH) could be detected, even though the

was no effective peripheral response; i.e. only the gonad

trophic sector was affected. In the acute phase there was

increase in LH liberation whilst testosterone was reduced,

contrast to the chronic phase, when both LH and testosteron

levels were diminished in the serum. In the light of such evi

ence, consideration has been given to the potential therapeut

use of secretagogues as part of a strategy rapidly to reverse th

inhibition of the hypothalamuspituitary system in critically

patients, leading to shortening of hospital confinement animprovement in the lifespan of these patients (Weekers and V

Den Berghe, 2004). Furthermore, studies on the hypothalamu

pituitary response in critical patients under chronic stress hav

led to the belief that similar mechanisms of inhibition might a

in amenorrhoeic diabetic women. Therefore, stimulation wi

secretagogues (i.e. GnRH) might help with the normalizatio

of gonadotrophic function in patients whose metabolic balan

has been improved but in whom the re-establishment of norm

menstrual cycles has not been accomplished.

Finally, we conclude that T1DM, like diabetes mellitus

general, must be considered in the differential diagnosis

amenorrhoea. Studies carried out to date have not clarified a

of the mechanisms involved in this disorder. The only cleevidence is for the augmentation of dopaminergic tonus wi

the consequent alteration in the menstrual cycle and in GnRH

FSH, LH and estradiol feedback. The hyperandrogenism com

monly associated with menstrual irregularities in non-diabet

women cannot be fully explained. Since most studies sugge

that there is an individual response to the improvement of gl

caemic control, it is worthwhile evaluating the hormonal stat

of those diabetic patients in whom menstrual irregularities pe

sist even though metabolic control has been improved. There

no conclusive evidence concerning the use of dopaminerg


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336

inhibitors for the treatment of diabetic patients suffering from

menstrual irregularities, although there is confirmation that the

use of hypothalamuspituitary secretagogues may have a nor-

malizing action on the HPO axis, which is chronically sup-

pressed in amenorrhoeic diabetic patients.

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Submitted on July 10, 2005; resubmitted on September 13, 2005; accepted September 20, 2005

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