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3 Treatment of Folliculo-Luteal Insufficiency with  Low-­Dosage Corticoid or Combined Corticoid and Clomiphene Citrate Therapy

3 Treatment of Folliculo-Luteal Insufficiency with  Low-­Dosage Corticoid or Combined Corticoid and Clomiphene Citrate Therapy

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4.4



Discussion



55



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.



4.4



Discussion



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.



56



4



Treatment of Folliculo-Luteal Insufficiency



33.7

31,0



30,3

35

5x100

CC



30



5x200

CC



5x150

CC



21,9

21,4



25

20



16,8



16,6



18,23



13,7

15



12 ,0



10,9

9,1



10

5

0



DEX +CC

5x200mg CC

5x150mg CC

5x100mg CC

basal value



* DEX +



DEX +



DEX +



500 CC



750 CC



1000 CC



35%



47%



18%



* 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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5



Recurrent Miscarriage and

Folliculo-Luteal Function



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,

DOI 10.1007/978-3-319-39540-1_5



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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).



5.1



Most Investigated Causes and Risk Factors of Recurrent

Miscarriage



5.1.1



Genetic Factors



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



5.1



Most Investigated Causes and Risk Factors of Recurrent Miscarriage



63



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.



5.1.2



Anatomical Factors



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.



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3 Treatment of Folliculo-Luteal Insufficiency with  Low-­Dosage Corticoid or Combined Corticoid and Clomiphene Citrate Therapy

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