By Borges, Lavinia Estrela Morgante, Giuseppe; Musacchio, Maria Concetta; Petraglia, Felice; De Leo, Vincenzo
Abstract Objective. To determine if a new protocol of administration of clomiphene citrate (CC) is effective in menstrual cycle recovery in women with hypothalamic secondary amenorrhea.
Design. This was an open-label study.
Patients. Patients comprised a group of eight women with secondary amenorrhea.
Interventions. An oral preparation containing CC (50 mg/day) was administered for 5 days followed by a double dose (100 mg/day) for another 5 days, initiated on day 3 after estrogen/progestogen- induced withdrawal bleeding. If ovulation and vaginal bleeding occurred, treatment continued in the two next months with 100 mg/ day from day 3 to day 7 day of the cycle.
Main outcome measures. Cycle control was evaluated at each visit, when patients recorded bleeding patterns and tablet intake. Data on the intensity and duration of bleeding were collected.
Results. Six patients responded to the first cycle of CC administration, resuming normal menstrual cycles. The other two patients failed to menstruate after the first 10 days of treatment with CC and repeated the same protocol. After the second administration, these two women also had normal menstrual bleeding.
Conclusions. The present data show that this new protocol of CC treatment may be useful to restore normal menstrual cycles in young women with hypothalamic amenorrhea.
Keywords: Clomiphene citrate, hypothalamic amenorrhea, cycle control
Introduction
Reproductive function is controlled by a very sophisticated system composed by the perfect synchronization of neuronal and endocrinological functions. Stress situations, due to physical, psychological or metabolic stressors, can negatively modulate the hypothalamus-pituitary-ovarian (HPO) axis, blocking ovarian activity [I]. A disruption at any point in one of the complex feedback interactions between the ovaries, pituitary and hypothalamus may lead to irregularities in the menstrual cycle [2]. In the face of extremely reduced nutrient intake, non-vital processes such as growth, pubertal development and reproduction are minimized until the nutritional situation improves [3].
Hormone replacement strategies have limited benefit because they do not promote recovery from these allostatic endocrine adjustments in the HPO axis. Although the menstrual pattern can be restored with exogenous administration of estrogen/progestogens, the long-term deleterious consequences of stress-induced anovulation may lead to increased risk of cardiovascular disease, osteoporosis, depression, and other psychiatric conditions [4]. Because some physicians use the return of menses to demonstrate regained health in these patients, they may not want to mask this outcome with the use of oral contraceptives. Therefore, evidence to date does not support the routine use of oral contraceptives in the management of patients with stress-induced amenorrhea and newer modalities may be a perspective [5]. Indeed, the rationale for the use of sex steroid replacement is based on the erroneous assumption that functional forms of hypothalamic hypogonadism represent only an alteration in the HPO axis, whereas behavioral and psychological interventions are also necessary to permit resumption of ovarian function along with recovery of the HPO axis [4] .
Clomiphene citrate (CC) has been applied as the first-line treatment in anovulatory women since the 1960s, due to its low cost and minor side-effects or complications [6] . It is recognized that CC has partial antagonist/partial agonist properties, and its dominant effect on the HPO axis is related to its antiestrogenic properties [7] . Thus treating patients with secondary amenorrhea with CC should correct their hormonal abnormalities. Frequently the classic protocol (100 mg/day for 5 days) does not improve the menstrual pattern and women continue to be amenorrheic, which can be explained by low endogenous levels of estradiol (E2). After two or three negative efforts this sort of treatment is abandoned and replaced with an estrogen/progestin oral contraceptive [8,9].
The present study was therefore designed to assess the cycle control of CC and its effects on ovarian activity in women with secondary amenorrhea due to hypothalamic dysfunction.
Materials and methods
This open-label study evaluated the effect of CC on cycle control in women with secondary amenorrhea (bleeding interval >6 months). The study was approved by the Institutional Review Board of our center. Informed consent forms were signed by all subjects prior to enrollment.
From March 2004 and November 2004, a total of eight patients (age range 17-22 years) were enrolled (Table I), including five women who practiced intensive exercise and three who had lost weight after a restrictive diet. Serum E^sub 2^ levels varied between 18 and 25 pg/ ml. An additional inclusion criterion was low serum follicle- stimulating hormone (FSH) levels. Exclusion criteria consisted of the presence of any endocrine abnormality. A complete medical, gynecological and obstetric history was obtained from each patient before initiation of CC therapy. Physical and gynecological examinations were performed and body mass index (BMI) was calculated for all subjects. Endocrine screening included serum assays of FSH, luteinizing hormone (LH), prolactin (PRL), thyroid-stimulating hormone (TSH), (E2) and progesterone (P), performed before CC treatment and on the third month during the treatment (day 3). Transvaginal sonographic screening included assessment of the ovarian stroma echogenicity, ovarian volume, and total number of follicles. Concomitant use of medication and adverse events were registered.
Table I. Characteristics of subjects (n = 8).
CC medication was initiated on day 3 after estrogen/progestogen- induced withdrawal bleeding. All subjects received an oral preparation containing CC 50 mg/day for 5 days followed by 100 mg/ day for another 5 days. If ovulation and vaginal bleeding occurred, treatment continued in the two next months with 1 00 mg/day from day 3 to day 7 of the cycle; if not the same treatment was repeated. Cycle control was evaluated on each visit when patients recorded bleeding patterns and tablet intake. Data on the intensity and duration of bleeding were collected. The duration of follow-up for all patients included in this study was 6 months. Ovulation was assessed by mid-luteal serum P measurement (level > 25 nmol/1) combined with transvaginal sonographic endometrial thickness assessment.
Serum LH and FSH concentrations were determined using a double- antibody radioimmunoassay (Sorin, Saluggia, Italy) and immunofluorimetric assay, as described previously [10,11]. Serum TSH, PRL, E^sub 2^ and P concentrations were determined using a commercially available radioimmunoassay (Radim RIA; Pomezia, Rome, Italy). The samples were assayed in duplicate at two dilutions. All samples from each participant were assayed together. Intra-assay and inter-assay variations were 6.2% and 6.5% for FSH, 7.8% and 8.2% for LH, 4.2% and 4.9% for E^sub 2^, and 8.5% and 10.8% for P, respectively.
Results are expressed as mean +- standard deviation. Comparison between data was performed by the signed rank test because of the small size of the sample. Statistical significance was set at p
Results
Among the eight patients with secondary amenorrhea due to hypothalamic dysfunction, six patients responded to the first cycle of CC administration and resumed normal menstrual cycles. The other two patients failed to menstruate after the first treatment with CC; however, a normal menstrual pattern was recovered after a second cycle with the same protocol. Serum LH and P levels increased significantly (p
Serum PRL and TSH did not show any significant change during CC administration (Table II). At 6 months’ follow-up, all patients had resumed menses. The patients did not change their diet during therapy and their weight changed during treatment by 12 kg. No significant differences were seen in body weight, BMI or percent body fat at follow-up.
Discussion
The present data show that this treatment protocol with CC may be useful to restore normal cycles in young women with hypothalamic amenorrhea. In some selective cases this protocol may be an alternative to administration of estrogen/progestogens to correct menstrual abnormalities and restore ovulation.
Figure 1 . Serum levels of luteinizing hormone (LH) and progesterone (P) before and during treatment with clomiphene citrate (CC). Values are means, with standard deviation shown by vertical bars. Mean values were significantly different: *p
Reduced availability of metabolic fuel below a critical level due to food restriction or increased energy expenditure is accompanied by the activation of multiple neuroendocrine/metabolic changes resulting in anovulation and amenorrhea [12]. Selective estrogen receptor modulators are compounds which may function as agonists or antagonists depending upon the target tissue and the protocol of administration [13]. CC seems to display both selective agonist and antagonist activity at the gonadotrope level and on gonadotropin- releasing hormone self-priming of LH secretion. Despite the widespread acceptance of CC as a therapeutic agent for ovulation induction, its effects on other estrogen-dependent pathways, particularly on neural circuits regulating brain function and peripheral hormone secretion, are poorly understood. Figure 2. Serum levels of follicle-stimulating hormone (FSH) and estradiol (E2) before and during treatment with clomiphene citrate (CC). Values are means, with standard deviation shown by vertical bars. Mean values were significantly different: *p
Table II. Hormonal parameters of the patients (n = 8).
This is the first study to provide additional information on gonadotropin response after a 10-day, step-up, CC administration protocol in patients with functional amenorrhea. After the first cycle of CC administration six patients resumed spontaneous menstrual cycles and all subjects had a significant rise in LH secretion after the second cycle of treatment, suggesting the resumption of ovulation. All subjects continued to have spontaneous menstrual cycles 6 months after beginning the treatment. A normal response to CC in amenorrheic patients with functional amenorrhea offers reassurance that the HPO axis is intact and that the problem lies in the hypothalamus. It is reasonable to believe that nutritional disturbances, food intake and persisting psychological factors still affect reproductive function in patients with amenorrhea [14].
Psychological factors in addition to nutritional status contribute to the prolonged amenorrhea in anorexia nervosa, and CC appears to have only a limited role in the treatment and management of patients with the disorder [9]. Administration of exogenous estrogen/progestin combinations to women with functional hypothalamic amenorrhea does not appear to result in increased bone density in this severely undernourished state [15,16], showing the importance of endogenous gonadal function in the preservation of bone mass in these subjects.
The administration of CC was shown to be more efficacious than placebo for ovulation induction in patients with functional hypothalamic amenorrhea and patients with amenorrhea of less than 1 year responded better to CC than patients with prolonged amenorrhea, with noted high serum FSH and LH levels [17,18]. CC acts as an estrogen antagonist on the neural circuits controlling the neuroendocrine regulation of the HPO axis [19]. The gonadotropic response cannot be explained only by the classic antagonist effect, but we can predict that the step-up protocol of CC administration could have sensitized the HPO axis, permitting the resumption of menses. Even though the sample size in this study is limited and the population heterogeneous, the present results offer new insights for future investigation in a larger group of women affected by hypothalamic amenorrhea, a condition which is becoming very common but has poor therapeutic efficacy.
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LAVINIA ESTRELA BORGES, GIUSEPPE MORGANTE, MARIA CONCETTA MUSACCHIO, FELICE PETRAGUA, & VINCENZO DE LEO
Section of Obstetrics and Gynecology, Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena,
Siena, Italy
(Received 28 December 2006; revised 28 February 2007; accepted 5 March 2007)
Correspondence: V. De Leo, Chair of Obstetrics and Gynecology, University of Siena, Policlinico ‘Santa Maria alle Scotte’, Viale Bracci, 1-53100 Siena, Italy. Tel: 39 0577 233 465. Fax: 39 0577 233 464. E-mail: deleotaunisi.it
Copyright Taylor & Francis Ltd. Jun 2007
(c) 2007 Gynecological Endocrinology. Provided by ProQuest Information and Learning. All rights Reserved.
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