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2 Controlled Clomiphene Citrate Treatment of  Folliculo-­Luteal Insufficiency

2 Controlled Clomiphene Citrate Treatment of  Folliculo-­Luteal Insufficiency

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4.2



Controlled Clomiphene Citrate Treatment of Folliculo-Luteal Insufficiency



51



spontaneous LH peak or to the administration of HCG (Agarwal and Buyalos 1995;

Deaton et al. 1997; Zreik et al. 1999; Vlahos et al. 2005). After achieving physiological FLF, we counselled the couples about the optimal time for cohabitation based on

the current length of the cycle that emerged during treatment, or in some cases, on the

results of urinary LH tests. By omitting serial ultrasound scans, the treatment protocol becomes substantially more simple, and based on our experiences, this does not

decrease the chances for success. Rather, it is the presence of controlled physiological cycles that seems essential for treatment success. We achieved physiological

pregnancy rates by applying the treatment as described above: in case of unexplained

infertility, the average monthly pregnancy rate over 12 months was 26 %, and the

yearly cumulative pregnancy rate was 98.5 % (Chap. 6).

We used CC treatment in the traditional way, between the 5th and 9th day of the

cycle, even though many authors have since switched to treatment between the 3rd

and 7th cycle days. Administering CC earlier is based on the assumption that the

adverse effects of CC on the endometrium and the cervical mucus (competitive

antagonism) diminish by the time of ovulation. However, the efficacy of the treatment does not change when administration of the equivalent CC dose starts on the

2nd, 3rd, 4th or 5th cycle days (Wu and Winkel 1989). We noticed that the elimination of these negative effects depends on the E2 level induced by the treatment. At

the same time, we suggest that the relatively slow excretion of CC (CC level

decreases to 15 % in 5 days, ASRM 2006) is beneficial in the prevention of premature LH peak that is often detected during stimulation therapies (Dickey et al. 1998).

In menotropin treatment combined with CC (5th-9th cycle day), the occurrence of

premature LH peak decreases to almost a third: from 15.9 to 5.5 % (Al-Inany et al.

2010).

In unexplained infertility, we used CC treatment (Clostilbegyt, EGIS, Hungary)

uniformly in 50 or 100 mg dosage between the 5th and 9th days of the cycle, and we

controlled its effect with regular measurements of average luteal P. We gradually

increased the applied dose by 5 × 50 mg per cycle until the physiological average, or

the physiological minimum value, was reached. After we recognised the strong relationship between FLF and pregnancy outcome, we revised the P values characteristic of physiological FLF. We considered the average P values of cycles that resulted

in singular, mature and eutrophic newborns as physiological from the aspect of

reproduction. The luteal average of P in such cycles was 29.2 ± 3.1 ng/ml and the

physiological minimum was 23 ng/ml (average-2SD). We maintained the treatment

with the dose required to achieve the desired physiological P value until pregnancy

occurred. In nearly 20 % of patients, we found that despite applying the constant

dosage that was required for physiological FLF, FLF can vary significantly during

the consecutive cycles. Therefore, we controlled FLF in two cycles along with the

application of the treatment dosage required for physiological cycles, which made

the occasional adjustment of the treatment possible. We also checked the effect of

the set CC dose every three cycles until conception took place.

The most important proof of every treatment procedure is its clinical effectiveness. We successfully used controlled CC treatment in treating unexplained infertility and also in habitual abortion. In the following chapters, we will describe the



52



4



Treatment of Folliculo-Luteal Insufficiency



clinical efficacy of CC treatment in detail. The success of treatment evidently

depended on FLF. Because of this, this chapter primarily covers the analysis of the

general rules and principles of CC treatment required to achieve physiological FLF,

which appears to be the most fundamental issue regarding clinical efficacy. In our

opinion, it is the lack of proper quantitative control that can explain the poor results

of empirical (uncontrolled) CC treatment. We analyse the main features of CC treatment mostly concerning the treatment of patients suffering from unexplained infertility, although we also evaluate our experiences regarding the treatment of patients

with habitual abortion.

CC treatment of FLI-induced infertility (N = 443) with 5 × 100 mg initial dose

caused the average luteal P to undergo a significant (p < 0.001) increase in our randomly selected patient population: from 11.8 ± 3.6 ng/ml to 24.6 ± 4.8 ng/ml. CC

treatment of 5 × 100 mg dosage resulted in physiological FLF in 53 % of the patients

(average p > 23 ng/ml). In 47 % of the patients, we achieved physiological FLF by

increasing the CC dose (Fig. 4.1).

In cases of habitual abortion (N = 370), 5 × 100 mg CC lead to highly significant

increase (from 12.2 ± 3.0 ng/ml to 23.0 ± 7.1 ng/ml), yet it only hit the physiological

value in 40 % of the patients. FLF normalised by administering 5 × 150 mg CC in

53 % of the patients and 5 × 200 mg in 7 %.



31.9



31.4

35



30.6

29.6

23.9



30

20.9



25



20.7



18.4

20

15



15.1

12.7

10.5



10

5

0



16.6



9.7



9.4



5x250mgCC

5x200mg CC

5x150mg CC

5x100mg CC

basal value



* 500 CC

750 CC 1000 CC

1250 CC

53%

35%

9%

3%

* doses required to achieve phisiological folliculo-luteal function



Fig. 4.1 Clomiphene citrate (CC) dosage* required to reach the physiological luteal minimum

(PROG > 23 ng/ml) in FLI (N = 443)



4.2



Controlled Clomiphene Citrate Treatment of Folliculo-Luteal Insufficiency



53



CC treatment procedures could be simplified if we knew any parameter that

could be the basis of predicting the effect of CC treatment. In light of this, we investigated the relations between the responses of several clinical and hormonal features

for CC treatment. If we analyse the characteristics of patients on the basis of the CC

doses required to achieve physiological luteal P, only the baseline P values differ

significantly between the different groups (Table 4.1). When comparing clinical and

other hormonal characteristics of patients, we failed to demonstrate any significant

difference between the age, body weight, BMI, occurrence of hyperandrogenism

and the values of the examined hormones (prolactin, cortisol, testosterone, SHBG,

free testosterone, androstenedione, DHEA-S). There was a significant difference in

the baseline P values, but the extent of this is so slight that it does not aid in clinical

practice in any way.

It can be concluded from the above that although the individual effect of CC varies greatly, it is always dose dependent in any given patient. With gradual, controlled increase of the dosage, physiological FLF can be achieved in each case. Thus

it is absolutely necessary to apply the treatment together with P control. This probably accounts for the poor results of uncontrolled, fixed-dosage CC treatment (most

commonly 5 × 50 mg, or 5 × 100 mg) and the often unfavourable pregnancy outcomes as well. Even if controlling FLF with a single P value during CC treatment

seems insufficient, authors who apply this achieve higher pregnancy rates, contrary

to authors who use CC treatment without control (see above). By recognising the

close relation of FLF and pregnancy outcomes (Chaps. 5 and 7), on this basis we

can understand why high abortion rates (14–23 %) occur during treatment applied

without proper control.



Table 4.1 Clinical and hormonal characteristics in folliculo-luteal insufficiency based on clomiphene citrate (CC) doses required to achieve physiologic luteal values



Characteristics

Age (years)

Weight (kg)

BMI (kg/m2)

Hyperandrogenism

Progesterone (ng/ml) (nmol/l)

Prolactin (mIU/l)

Cortisol (nmol/l)

Testosterone (nmol/l)

SHBG (nmol/l)

Free testost. (pmol/l)

Androstenedione (nmol/l)

DHEA-S (μmol/l)



5 × 100 mg

CC

N = 154



5 × 150

CC

N = 97



5 × 200

CC

N = 18



28.9 ± 4.0

59.0 ± 9.3

21.8 ± 1.4

12.3 % (19/154)

11.2 ± 3.4

35.6 ± 10.8

483 ± 332

381 ± 102

2.22 ± 0.97

114 ± 51

40.9 ± 24.5

6.63 ± 2.90

4.48 ± 2.20



29.9 ± 4.3

59.8 ± 10.0

22.3 ± 1.6

9.4 % (9/97)

10.2 ± 3.2*

32.4 ± 10.2

616 ± 310

419 ± 132

2.05 ± 0.88

118 ± 77

39.6 ± 28.8

7.12 ± 3.52

4.45 ± 2.10



29.3 ± 4.5

59.6 ± 10.1

22.2 ± 1.5

11.1 % (2/18)

8.1 ± 2.8**

25.8 ± 8.9

445 ± 248

367 ± 138

1.80 ± 0.74

96 ± 55

29.1 ± 11.1

6.60 ± 1.43

3.58 ± 1.28



Significance, compared to the P value of the previous group: *p < 0.05, **p < 0.01



5 × 250

CC

N=5

28.6 ± 3.5

61.5 ± 12.6

22.8 ± 1.5

20 % (1/5)

8.4 ± 3.8

26.4 ± 12.1

438 ± 324

436 ± 119

2.10 ± 0.87

105 ± 34

33.2 ± 22.7

6.35 ± 2.49

4.00 ± 2.07



54



4.3



4



Treatment of Folliculo-Luteal Insufficiency



Treatment of Folliculo-Luteal Insufficiency with

Low-Dosage Corticoid or Combined Corticoid

and Clomiphene Citrate Therapy



In our studies regarding the causes of FLI, we found that its main cause is the

enhanced activity of the hypothalamic-pituitary-adrenal (HPA) system induced by

stress (Chap. 3). The increased HPA activity primarily acts through the inhibiting

effect of CRH on GnRH secretion and the complete hypothalamic-pituitary-ovarian

(HPO) system and leads to the hormonal insufficiency of the menstrual cycle.

Androgens produced by the adrenal cortex and the extraovarian oestrogens that are

converted from them on the periphery also play some role in this process, especially

in the case of overweight people. The beneficial effect of low-dose dexamethasone

(DEX) treatment seems to confirm this pathomechanism. It resulted in a significant

(p < 0.001) increase of average luteal P in cases either with or without hyperandrogenism (HAN) (Table 3.2 and 3.3). The positive effect of low-dose DEX treatment proved the primary causal role of stress in the development of FLI. Based on

this, we applied low-dose DEX treatment – which can be viewed as a causal treatment – in clinical practice as well (Fig. 4.2).



33.1

27.3

35

27.4

30

19.1

25



20 .3

15.5



20

15



13.4



11.9



11.7



10



DEX+5x100mgCC

DEX+5x50mg CC

DEX (0,5 mg/nap)

basal value



5

0

* DEX

45%



DEX +

250mg CC



DEX +

500 mg CC



51%



4%



* doses required to achieve phisiological folliculo-luteal function



Fig. 4.2 Treatment of folliculo-luteal insufficiency with low-dosage corticoid or combined

corticoid and clomiphene citrate therapy



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.



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