Neurol Sci (2006) 27:231239

DOI 10.1007/s10072-006-0676-x

REVIEW

P. Cavalla V. Rovei S. Masera M. Vercellino M. Massobrio R. Mutani A. Revelli

Fertility in patients with multiple sclerosis: current knowledge

and future perspectives

Received: 15 March 2006 / Accepted in revised form: 7 July 2006

Abstract The issue of fertility in patients with multiple Introduction

sclerosis (MS) has not been exhaustively studied.
Epidemiological data have suggested that spontaneous
fecundity might be reduced; several endocrine and sexual
disturbances potentially interfering with reproduction
have been evidenced in MS patients of both sexes.
Moreover, some medical treatments used in MS (e.g.,
mitoxantrone, cyclophosphamide) may exert detrimental
effects on spermatozoa as well as on oocytes, leading to
early impairment of fertility. This review illustrates the
factors potentially interfering with fertility in MS and dis-
cusses the therapeutic tools that may be used to promote
fertility in these patients. The safety of hormonal therapies
in MS is also examined. The current applications of assist-
ed reproductive technology (ART) are discussed, includ-
ing in vitro fertilisation (IVF) techniques. Currently avail-
able methods to preserve fertility in patients that undergo
cytotoxic treatments by means of sperm/oocyte cryostor-
age or by ovarian fragment cryopreservation and auto-
grafting are considered.
Key words Multiple sclerosis Mitoxantrone Fertility In with minimal disability: a decreased relapse rate during
vitro fertilisation Sperm cryostorage Oocyte cryostorage
V. Rovei M. Massobrio A. Revelli ()
Reproductive Medicine and IVF Unit
Department of Obstetrical and Gynaecological Sciences
University of Turin
Via Ventimiglia 3, I-10126 Turin, Italy
e-mail: fertisave@yahoo.com
P. Cavalla S. Masera M. Vercellino R. Mutani istry [8]; this might reflect, rather than lowered fertility,
Department of Neurosciences
University of Turin, Italy
Multiple sclerosis (MS) is primarily a demyelinating
T-cell-mediated chronic inflammatory disease of the cen-
tral nervous system (CNS), in which an autoimmune
response to myelin proteins of the CNS is triggered by one
or more exogenous agents in a genetically susceptible host
[1]. Clinical manifestations, represented by either focal or
multifocal, transient or persistent signs and symptoms,
appear usually around 2040 years of age [1]. MS is more
frequent in women than in men, with a female-to-male
ratio between 3:1 and 2:1 [2]. As a consequence, MS fre-
quently involves young people (particularly women) in
their childbearing age.
Sex steroid and reproductive events may have an impact
on the course of MS: a possible role of sex hormones in
modulating disease activity and brain damage has been
recently shown [3, 4]. The role of pregnancy in MS has
been discussed for a long time [5]. Short-term effects have
been outlined in the PRIMS study on 254 women with the
relapsing-remitting (RR) form, predominantly young and
pregnancy and an increased relapse rate during the post-
partum period were observed, with an almost neutral over-
all effect [6, 7]. Moreover, the progression of disability up
to 2 years post-partum was not different from that expected
in women with minimally disabling MS [6]. Pregnancy
might even exert a positive influence on the course of MS
in the long run, leading to a reduced risk of transition to the
secondary progressive (SP) phase [8].
The issue of fertility in MS has not been exhaustively
studied. Few data can be found in papers not specifically
focused on this topic [5, 811]. The frequency of child-
lessness in the MS female population might be higher than
in the general population, as suggested by the Swedish reg-
the fact that patients with disability may choose to avoid or
postpone pregnancy, mainly because of concern about tak-
232
ing care of the baby. Some patients of fertile age may also
be concerned about the risk of transmitting a genetical sus-
ceptibility to MS to their children. However, sexual com-
petence and peculiar endocrine patterns might be relevant
in terms of fertility. If many immunosuppressive therapies
have a negative effect on fertility, the impact of the widely
used immunomodulating treatments is less clear. Because
of the high prevalence in Western countries of infertility
(about 15%20% of couples) and MS in fertile age, it is
possible that a patient with MS could belong to a couple
that seeks treatments for infertility, even if infertility is not
a direct result of MS. For all these reasons, it is worth per-
forming a more complete analysis of fertility in MS
patients.
Factors potentially affecting fertility in MS
Sexual dysfunctions
Sexual dysfunctions (SDs) are often undeclared by
patients with MS, although they represent a frequent cause
of dissatisfaction with a negative impact on the quality of
life [12]. Recent studies show a variable incidence of SDs,
ranging from 30% to 70% of patients, depending on the
clinical characteristics of the studied population and on the
duration of follow-up [13]. SDs in these patients may be a
direct consequence of MS, due to incompetence in organ-
ising and integrating the complex phases of sexual
response, or may depend on the emotional problems sec-
ondary to the disease.
The most frequently described SDs in women include
reduced libido (36%86% of cases), difficulty in achieving
orgasm (28%58%), reduction in the tactile sensations
originating from the thigh and genital regions (43%62%)
and vaginal dryness with consequent dyspareunia
(8%40%) [1315].
In men, frequent SDs include reduced libido
(37%86%), erectile dysfunctions (34%80%) ranging
from smooth and inconstant to intense and persistent,
reduction in tactile sensations (21%72%), ejaculatory
dysfunction (34%61%) and reduced orgasmic capacity
(29%64%) [13, 14]. Erectile and ejaculatory dysfunctions
might be partially correlated to the reduced testosterone
blood levels reported in MS patients [16, 17]. Reduced
orgasmic capacity may depend on several factors including
sensitivity defects, problems in concentration, fatigue and
spasticity. In both sexes, bladder and bowel incontinence,
weakness, indwelling catheters, visual defects and speech
disturbance may also affect sexual activity, interfering
with social relationships and with intimate behaviour [16].
The patients age, as well as the duration and type of
MS, shows a limited degree of correlation with SDs; SDs
and disability score or motor deficits correlate better,
P. Cavalla et al.: Fertility in MS patients
whereas a highly significant correlation has been shown
between SDs, sensitivity defects and urinary/bowel distur-
bances [13]. SDs seem to be dependent on the degree of
spinal impairment, as the neural areas controlling the uri-
nary function are strictly related to those controlling sexu-
al activity [18].
Endocrine pattern
Men affected by MS have been reported to have reduced
testosteronaemia [16, 17, 19], potentially affecting sperm
production. Low testosterone levels in the general circula-
tion, however, impact libido and sexual competence more
than the quality of semen, as good spermatogenesis may be
accomplished even with subnormal testosteronaemia [20].
In women, central influences on the hypothalamus and
the pituitary gland may lead to dysfunctions of the repro-
ductive axis, clinically appearing as menstrual irregularity
and infertility. Women with MS were shown to have sig-
nificantly higher follicle stimulating hormone (FSH) and
luteinising hormone (LH) levels, and significantly lower
oestrogen levels in the early follicular phase of the men-
strual cycle [21]. Interestingly, FSH levels in the early fol-
licular phase are strongly related to the extent of the ovar-
ian reserve; circulating FSH levels above 10 UI/l are con-
sidered a marker of reduced ovarian reserve, whereas FSH
levels above 15 UI/l indicate a pathologically low ovarian
reserve [22]. A low ovarian reserve is strongly correlated
to female infertility due to poor oocyte quality, which can-
not be overcome even with the most sophisticated repro-
ductive technologies [23].
It is unknown whether the autoimmune mechanisms
related to MS could affect the ovary, leading to a more pre-
cocious consumption of the ovarian reserve, but a similar sit-
uation occurs in autoimmune hypothyroidism, which is asso-
ciated with a higher risk of oocyte-linked infertility, abortion
and precocious ovarian failure (POF) [24]. Interestingly,
6%8% of MS patients have a concomitant thyroid dysfunc-
tion, more frequently hypothyroidism [25]. Therefore,
women with MS might have some degree of predisposition
to developing POF. The clomiphene citrate test [26] could be
used to diagnose this at-risk condition early and eventually
advise women to schedule their pregnancies at younger ages.
In women with MS, other studies reported a higher
incidence of hyperprolactinaemia [21] and of signs and
symptoms of hyperandrogenism: increased levels of
androstenedione, total and free testosterone [21], higher
incidence of greasy skin, acne and hirsutism [27]. These
alterations could contribute to the slightly higher incidence
of oligo/amenorrhoea observed in women with MS (20%
vs. 16% of control subjects) in one of these studies [27].
This endocrine pattern is similar to that observed in poly-
cystic ovary syndrome (PCOS), frequent in fertile women.