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3 Treatment of Folliculo-Luteal Insufficiency with Low-Dosage Corticoid or Combined Corticoid and Clomiphene Citrate Therapy
While other researchers complement CC treatment with DEX treatment applied
in a defined part of the cycle (2 mg/day dose between the 5th and 15th cycle day,
Moradan and Gharbani 2009) to treat unexplained infertility, we used continuously
administered DEX treatment of 0.5 mg dose every evening. In case of conception,
we stopped treatment when we obtained a positive pregnancy test result. We chose
continuous treatment as the decrease of GnRH secretion exerts a negative effect in
each phase of the cycle. Inhibiting FSH levels at the beginning of the cycle disturbs
the emergence of a physiological cycle similarly to the negative effects on the LH
peak or on the essential LH secretion during the luteal phase. If the treatment is
applied in the evening, a lower dosage is sufficient to achieve the desired effect due
to the early morning maximum cortisol secretion. Moreover, daily treatment with
0.5 mg of DEX involves no risks, and the development of any considerable adverse
side effects is unlikely during its application (ASRM 2006).
Continuous, low-dose DEX treatment alone was primarily used in patients who
exhibited HAN (hirsutism with elevated free testosterone levels) besides FLI and, in
cases with cycles that were unstable, varying in length or oligomenorrhoeal. FLF
normalised in 45 % of patients with DEX treatment alone (average p > 23 ng/ml). In
51 % of patients, FLF normalised by adding 5 × 50 mg CC and in 4 % of patients by
adding 5 × 100 mg CC (Fig. 4.2).
We used combined CC + DEX treatment (first CC alone and then CC + DEX)
primarily in patients who responded poorly to CC treatment compared to the average. In all three groups in which we complemented 5 × 100 mg (35 %), 5 × 150 mg
(47 %) and 5 × 200 mg (18 %) CC treatment with DEX, a very positive effect was
observed, with P values over 30 ng/ml (Fig. 4.3). On this basis, in case of insufficient CC efficacy, it seems reasonable to complement the treatment with DEX even
at a dose of 5 × 100 mg CC if this causes a moderate P increase.
We found an especially beneficial effect of DEX complementation in patients
whose measured P values varied under identical CC dosage. It is presumably the
varying intensity of stress that underlies the different treatment responses of such
cases, the effect of which is favourably diminished by DEX treatment.
As the causal role of enhanced adrenal cortex function in the development of associated reproductive function disorders is already accepted in HAN cases (hirsutism,
increased androgen secretion), corticoid suppression of the HPA axis has been used
to treat these conditions for decades (Greenblatt 1953; Jones et al. 1953). The normalisation of cycle disturbances was observed in 60–100 % of the cases as an effect
of DEX or prednisone treatment (Abraham 1981; Yuen and Mincey 1983; Birnbaum
and Rose 1984), and conception took place in 66 % of the cases (Casey et al. 1966).
Sarries et al. (1978) achieved 55 pregnancies – only 5 (9 %) out of which ended in
abortion – with continuous prednisone treatment in 30 patients with an anamnesis
of 20 (91 %) abortions out of 22 pregnancies, which supports the causal role of
adrenal HAN in associated FLI and the occurrence of abortion it causes.
Treatment of Folliculo-Luteal Insufficiency
* DEX +
* doses required to achieve phisiological luteal function
Fig. 4.3 The required dose of combined clomiphene citrate (CC) and dexamethasone (DEX)
treatment to achieve physiological FLF * (N = 85)
Many authors achieved positive results by CC treatment complemented with
DEX or prednisolone in the case of anovulation or PCOS (Lobo et al. 1982; Daly
et al. 1984; Trott et al. 1996; Isaacs et al. 1997; Elnashar et al. 2006). In literature
reviews (Cochrane database), completing CC treatment with DEX seemed remarkably favourable against CC treatment alone (OR 9.46) in PCOS and in anovulatory
conditions without PCOS as well (Beck et al. 2005; Brown et al. 2009). Combined
CC + DEX treatment of unexplained infertility is only reported in the publication of
Moradan and Ghorbani (2009). Better monthly pregnancy rates were achieved by
CC + DEX treatment than by CC treatment alone (21.4 % and 4.5 %, respectively).
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Treatment of Folliculo-Luteal Insufficiency
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Recurrent Miscarriage and
The term “recurrent miscarriage” means the abortion of two or more consecutive
pregnancies before the 24th week (the foetus is <500 g and/or <30 cm, ASRM 2008,
2013). In the past (but in many cases, even today), the diagnosis was made after
three or more spontaneous abortions (Berry et al. ETEP 1995; ESHRE/ASRM
2006). The abortion of two or more consecutive pregnancies occurs in 5 % of women
and of three or more in 1–3 %. In Hungary, two abortions are considered the criteria
for recurrent miscarriage from the beginning (Zoltán 1975; Papp 1999). Using these
criteria can be supported by the fact that adequate treatment applied after two abortions (see later) can prevent abortion, preterm birth and IUGR in 90–98 % of women
during the third pregnancy compared with those conceived without intervention.
Very few disorders of such importance have provoked the publication of so many
contradictions, inaccuracies and unfounded assumptions as recurrent miscarriage
(Stirrat 1990). Many authors have researched the role of genetic, immunologic, anatomical, endocrinological and other factors in the development of recurrent miscarriage (RM); nevertheless, no common view has yet emerged regarding their actual
causal role. We do not know any reason that would cause abortion in every subsequent pregnancy. This uncertainty is well indicated by the fact that almost 10,000
papers concerning RM have been published in recent decades, and the rates of successful childbearing have refused to change despite various therapeutic attempts.
From the patients of the University Clinic of Copenhagen who receive treatment for
recurrent miscarriage, 66 % give birth within 5 years and only 71 % within 15 years
(Lund et al. 2012). These results do not actually differ from the results of untreated
patients. In our patient material, 56 % of patients with a history of 3–9 abortions
give birth after the next pregnancy without treatment, and if we factor in the repeated
pregnancies of a proportion of patients, this ratio is approximately 70 %. The diagnostics of RM thus means discovering the risk factors that – if eliminated – we hope
will allow for a better prognosis (whereas not even a presumed risk factor can be
demonstrated in almost half of the patients and the abortion rates in this group are
similar to those of with almost any risk factor).
© Springer International Publishing Switzerland 2016
G. Siklósi, Role of Folliculo-luteal Function in Human Reproduction,
Recurrent Miscarriage and Folliculo-Luteal Function
Two certain connections are known regarding the outcome of subsequent pregnancy. First, the recurrence rate of spontaneous abortions increases in proportion to
the number of abortions in the medical history of the patient in question, and second,
abortions occur more frequently in parallel with maternal age (especially in patients
older than 35). Additionally, the extraordinary importance of RM in obstetrics arises
from the fact that the occurrence of preterm birth, intrauterine growth retardation
(IUGR) and foetal malformations, etc. increases by two to four times in parallel with
the number of abortions (Reginald et al. 1987). The most common causes of abortions – independent from the presence or absence of risk factors – are currently randomly occurring chromosomal abnormalities, usually numerical disorders that can
be detected in approximately 50 % of aborted pregnancies (Christiansen et al. 2005;
Branch et al. 2010; Tang and Quenby 2010; Sugiura-Ogasawara et al. 2014).
Most Investigated Causes and Risk Factors of Recurrent
Currently the most common (approximately 50 %) causes of recurrent miscarriage
(RM) are randomly occurring chromosomal abnormalities (CA), usually of numerical nature (90 %) (primarily trisomy, polyploidy, monosomy) that emerge during the
first two meiotic and the subsequent first three mitotic cell divisions of the oocyte.
The occurrence of CAs is thought to be more frequent in sporadic abortions (60–
70 %) by most authors, although van der Berg et al. (2012) found a 45 % occurrence
when summarising the data of 13 studies involving 7012 abortion cases. As maternal age increases, the occurrence of CAs increases rapidly, reaching up to 78 %
(Marquard et al. 2010). The ratio of these chromosomal abnormalities falls to
20–33 % in abortions between the 13th and 24th week (Rai and Regan 2006; Branch
et al. 2010; Tang and Quenby 2010; van der Berg et al. 2012). In a large patient
population, Ogasawara et al. (2000) showed that the number of abortions with normal karyotype rises relative to the number of abortions in the anamnesis; thus the
occurrence of numerical CAs is almost constant, independent of the number of
abortions (approximately 20 % calculated for all pregnancies). At the same time,
this means that with treatments initialised after conception, a maximum live-birth
rate of 80 % can be achieved in RM.
Structural chromosomal abnormalities are present in about 2 % of couples with
recurrent miscarriage, compared to 0.2 % in the average population. They occur in
less than 1 % in uncompensated form during the second trimester and in case of live
birth at a similar rate as in cases without abnormalities. Barber et al. (2010) detected
compensated translocation in 406 (1.9 %) of 20,432 childbearing patients with
recurrent miscarriage, and they found uncompensated chromosomal abnormalities
in four cases (1 %) out of this group. Uncompensated abnormalities occur in only
about 12 % of abortions with structural chromosomal abnormalities (in 4 % of total
pregnancies involved), and in almost half of the abortion cases, no chromosomal
Most Investigated Causes and Risk Factors of Recurrent Miscarriage
abnormalities can be detected. In the remaining cases, numerical CAs were found
(Desjardins and Stephenson 2012; Kochhar and Ghosh 2013). In light of these facts,
these authors question the necessity of routine chromosomal testing of parents, in
accordance with other researchers (Branch et al. 2010; Tang and Quenby 2010).
Therefore, it is likely that structural chromosomal abnormalities are rarely the cause
of repeated, consecutive abortions.
Malformations resulting from the impaired fusion of the Mullerian duct (the most
common forms are subseptated, septated and bicornuate uterus) occur in approximately 4 % of patients with normal obstetric history whereas in 8 % of patients with
recurrent miscarriage (Sugiura-Ogasawara et al. 2010). In view of the structural
anomalies of the uterus, their role in the occurrence of abortions seems almost evident, although clinical experiences appear to contradict this. Even together with
these developmental abnormalities, a ratio of 60–70 % successful births can be
achieved in patients with several preceding spontaneous abortions (Acien 1993;
Kirk et al. 1993), and a higher success rate (60–75 %) is not even achieved after
metroplasty (Ayhan et al. 1992; Acien 1993; Fedele et al. 1993). Moreover, after
surgery, infertility emerged in 10–25 % of patients (Fedele et al. 1993). SugiuraOgasawara et al. (2010) found that in women with 2–12 abortions, the live-birth rate
of the first pregnancy following examination was lower than in recurrent miscarriage patients with normal uterine cavities (59.5 % and 71.7 %), although the difference in cumulative birth rates was not significant after three pregnancies (70.8 and
85.5 %). In patients with uterine cavity alterations whose pregnancies ended with
abortion or birth, it was mainly the D/C ratio (septum length/remaining uterine cavity length) that showed significant differences, as other authors have also stated
(Salim et al. 2003; Sugiura-Ogasawara et al. 2010). It is also against the primary
causal role of septated uterine cavities that after the complete, controlled hysteroscopic resection of the septum, the rate of abortions hardly changes (34.1 %) and
conception occurs only in 65 % of patients over 3 years (Paradisi et al. 2011). In
mature births after septum resection, the weight of the newborn is significantly
lower than in women with normal uterine cavities (Agostini et al. 2009).
Out of 1000 couples, 50 (5 %) are likely to suffer from RM. Therefore, in 50
women with recurrent miscarriage, the above-mentioned anomalies are expected to
develop in four (8 %) and in 38 (4 %) of the remaining 950 couples. Thus, the question arises: why only approximately every 10th woman with uterus alteration will
develop recurrent miscarriage? It seems plausible that causal factors other than uterine cavity abnormalities are required for the development of habitual abortion.
Moreover, in the presence of uterine abnormalities, 85 % of women with recurrent
miscarriage usually give birth in their third or fourth pregnancies (Jaslow et al.
2010). After their fourth pregnancy, only a small proportion did not give birth,
which is another factor that makes the primary causal role of these alterations doubtful in RM.