Differences in prescription rates and odds ratios of antidepressant drugs in relation to individual hormonal contraceptives: a nationwide population-based study with age-specific analyses.

OBJECTIVES: To examine, among young women, the association of individual hormonal contraceptives, within two broad groupings, with antidepressant therapy. METHODS: In a nationwide register-based study, we examined the prescription rates of antidepressant drugs in relation to individual combined hormonal and progestin-only contraceptives among Swedish women aged 16-31 years (N = 917,993). Drug data were obtained from the Swedish Prescribed Drug Register for the period 1 July 2005-30 June 2008. Data on the total population of women aged 16-31 in 2008 were obtained from the Total Population Register of Statistics Sweden. The proportion of women using both hormonal contraception and antidepressants, and odds ratios (ORs) for antidepressant use for hormonal contraceptive users versus non-users, were calculated, the latter by logistic regression, for each formulation. RESULTS: The highest antidepressant OR in all age groups, particularly in the 16-19 years age group, related to medroxyprogesterone-only, followed by etonogestrel-only, levonorgestrel-only and ethinylestradiol/norelgestromin formulations. Oral contraceptives containing ethinylestradiol combined with lynestrenol or drospirenone had considerably higher ORs than other pills. ORs significantly lower than 1 were observed when ethinylestradiol was combined with norethisterone, levonorgestrel or desogestrel. CONCLUSION: The association between use of hormonal contraceptives and antidepressant drugs varies considerably within both the combined hormonal contraceptive and the progestin-only groups.

Regressive liver adenomatosis following androgenic progestin therapy withdrawal: a case report with a 10-year follow-up and a molecular analysis.

OBJECTIVE: The relationship between sex hormones and hepatocellular adenoma development is well established. On the contrary, their contribution to liver adenomatosis (LA) development is still a debatable issue. Recently, inactivating mutations of hepatocyte nuclear factor-1alpha (HNF-1alpha) transcription factor gene or activating mutations of beta-catenin have been demonstrated in some liver adenomas, and a possible link between HNF-1alpha gene mutations and oral contraceptives has been suggested. Only two cases of regressive LA after hormone withdrawal therapy have been described so far but without any information concerning the molecular characteristics of the tumours. CASE: We report the case of a 48-year-old woman with LA, who had been taking an androgenic progestin therapy (lynestrenol) for 10 years. A major regression in the number and size of the lesions was observed 6 months after complete withdrawal of this therapy. METHODS: Hepatocellular adenomas were studied by immunohistochemistry for oestrogen, progesterone and androgen receptors (ER, PR and AR respectively), and for beta-catenin. Direct sequencing of the HNF-1alpha gene was also performed. RESULTS: For the first time, we demonstrate significant immunostaining of AR in the hepatocellular adenomas. This staining was negative in the partially regressive adenoma. Immunostainings for ER and PR were negative. HNF-1alpha and the beta-catenin pathways were not involved in tumour pathogenesis. CONCLUSIONS: Our case suggests a role of androgenic progestin therapy in some cases of LA. Hormone therapy withdrawal may induce a significant regression in lesions.

[Hormonal contraception and cervix of the uterus pathology].

The effect of hormonal contraception on cervix of the uterus of young nullipara women with ectopia was investigated. Cohort study was carried out by using simple blind method. By means of statistical data manipulation correlation between the application of hormonal contraceptives and changes of colposcopy pictures in the zone of pathology was displayed. Excluton showed low percent anomalous colpscopy picture in pathology zone. Excluton was declared as medicine of choice for nullipara women with ectopia. Still it is necessary to conduct a strong dynamic control of cervix of the uterus (colposcopy and pap-smear test) in order to avoid complications.

[Ectopia of cervix of the uterus and hormonal contraception].

The aim of the study was the investigation of impact of different hormonal contraceptive drugs on cervix of uterus of young nullipara women with ectopia. Cytologic smears were examined using Pappanikolau method. Cohort study was carried out by using simple blind method. The data were treated by statistics packet (SPSS). The results displayed correlation between taking the hormonal contraceptives Rigevidon and Marvelon and in transformation of ectopia into micro glandular hyperplasia, which did not occur in taking medicine Exluton. Drug Exluton is recommended for young nullipara women with ectopia to exclude micro glandular hyperplasia. In case of prescribing monophase contraceptives for young nullipara women with ectopia cytological control of endo- and exo-cervix is recommended.

[Multiple endometrial polyps in patient undergoing long-term gestagen therapy].

Endometrial polyps represent a limited focal, circumscribed overgrowth of the endometrium. Their aetiopathogenesis has not been completely explained yet. They are often found in perimenopausal women; during the reproductive period they are less common. We present the case of a 32-year-old patient, who came for a check-up to the Gynaecology and Obstetrics Clinic "Narodni Front" because of irregular bleeding. The patient was subjected to hormonal linestrenol therapy, which she had administered herself, without further consultations with her gynaecologist, during the previous 10 years. Complete diagnostic examinations were performed. Contrast sonohysterography enabled the visualisation of multiple polyps inside the uterine cavity, which were confirmed by histopathological analysis of material obtained via explorative curettage. Histopathological material contained over 30 endometrial polyps. A control check-up after one month, as well as subsequent quarterly check-ups, resulted in normal findings. Analysis of the described case has indicated that the loss of sensitivity of progesterone receptors in endometrial cells is possible if there is a continuous presence of progesterone agonists in circulation, as is true of linestrenol in this case. The loss of sensitivity of progesterone receptors upsets normal hormonal activity during the secretory phase of the menstrual cycle, leading to copious, irregular bleeding. These changes may, however, have even deeper effects. More recent research shows that, if the agent causing the loss of sensitivity of the receptors is present in circulation over a longer time period, changes may also appear at the DNA molecular level, i.e. in the cell genome itself. This, in turn, may lead to the beginning of the process of oncogenesis and the formation of tumourous tissue.

A 3-year double-blind, randomized, controlled study on the influence of two oral contraceptives containing either 20 microg or 30 microg ethinylestradiol in combination with levonorgestrel on bone mineral density.

In this first prospective, double-blind, randomized, parallel-group study we evaluated the influence of two combined oral contraceptives on bone mineral density (BMD) and metabolic bone parameters. One dose-reduced preparation contained 20 microg ethinylestradiol (EE) in combination with 100 microg levonorgestrel (LNG) (20/100) was compared with the reference preparation which contained 30 microg EE in combination with 150 microg LNG (30/150). Data from 48 volunteers aged 20-35 years were obtained over an observation period of 36 treatment cycles. The direction of the change (increase or decrease) in all investigated bone-related variables was similar in both treatment groups. As compared to baseline, bone mineral density decreased by 0.4% in the 20/100 group and by 0.8% in the 30/150 group after 36 treatment cycles. These changes were not significantly different between the two treatment groups (p = 0.902). For bone-specific alkaline phosphatase, we measured a mean increase of 55.4% (20/100 group) and of 113.2% (30/150 group) after 36 treatment cycles. The two treatments did not differ statistically significantly (p = 0.522). With respect to cross-linked N-telopeptides (NTx), we detected a decrease of the mean NTx urine concentrations of 21.1% (20/100) and of 13.4% (30/150). These changes also did not significantly differ between the two treatments (p = 0.613). Both study treatments were safe and well-tolerated by all volunteers participating in the study. In conclusion, BMD did not change during the 3-year observation period. Thus, both trial preparations containing either 20 or 30 microg EE in combination with LNG were capable of maintaining BMD in young fertile women. There is no reason to assume that the EE dose reduction had any negative impact on BMD. Because there were no differences in BMD between the treatment groups, it can be assumed that even lower dosages than 20 microg EE might be sufficient for bone protection. Biochemical markers provided evidence for a reduced bone resorption.

Prospective randomized study comparing the GnRH-agonist leuprorelin acetate and the gestagen lynestrenol in the treatment of severe endometriosis.

Endometriosis is thought to be an ovarian-dependent benign disease that affects up to 12% of women during their reproductive life. For the past ten years the gonadotropin-releasing hormone (GnRH)-agonists have been proved effective and safe drugs in the treatment of endometriosis. Nevertheless, gestagens such as lynestrenol still remain the most often used hormonal drugs for the treatment of this disease. The primary objective of this study was to compare the efficacy of the GnRH-agonist leuprorelin acetate depot (LAD) (Enantone-Gyn) 3.75 mg subcutaneously per month with that of the gestagen lynestrenol (LYN) (Orgametril) 5 mg orally twice per day in women with severe endometriosis, in terms of postoperative revised American Fertility Society (r-AFS) scores I-IV at first-look laparoscopy (score after removal of endometriotic lesions or adhesions) to the r-AFS score after six months' treatment. Secondary objectives were the improvement of clinical symptoms and the side-effect profile. Forty-eight women with postoperative r-AFS scores I-IV were evaluated in an open prospective randomized study between 1996 and 1998. All the participants underwent a first-look laparoscopy with resection of endometriotic lesions and six months' therapy with one of the above mentioned drugs, and a further second-look laparoscopy. The six months' treatment with LAD or LYN led to a significant reduction of the r-AFS score points in both groups. The mean r-AFS score in points for the LAD group after the first-look laparoscopy was 21.8 and was 27.2 for the LYN group. After the medical treatment a mean value of 11.5 points was observed in the LAD group compared with a mean value of 25.5 in the LYN group. This difference was statistically significant (p = 0.000014, Wilcoxon test). The improvement in the symptoms of dysmenorrhea, chronic pelvic pain and dyspareunia was also more pronounced in the LAD-treated group. LAD was more effective than LYN in the suppression of circulating serum 17 beta-estradiol levels after 6 months of treatment (mean 27.7 +/- 9.3 pg/ml versus 42.6 +/- 59.3 pg/ml). All the observed side-effects were deemed tolerable by the women who participated in this study. As the reduction of the r-AFS score in points was much more pronounced in the LAD group than in the LYN group, GnRH-agonists should therefore be used as first-choice drugs in the treatment of endometriosis. Due to the limited treatment of 6 months' duration of GnRH-agonists, gestagens might be used as second-line drugs for long-term and continuous treatment in the management of endometriosis to maintain the primary beneficial effect of GnRH-agonist treatment in patients who have completed their families.

Leuprorelin depot 3.75 mg versus lynestrenol in the preoperative treatment of symptomatic uterine myomas: a multicentre randomised trial.

OBJECTIVES: To compare the effect of the gonadotrophin-releasing hormone agonist leuprorelin and progestin lynestrenol, given prior to surgical treatment of symptomatic uterine myomas, on the pre-operative symptoms, tolerance, and operative blood loss. STUDY DESIGN: Fifty-six women were randomly selected to receive, during 16 weeks, either monthly subcutaneous injections of leuprorelin 3.75 mg sustained release (n=33) or lynestrenol 5 mg two tabs per day (5th to the 25th menstrual cycle) (n=23). RESULTS: Intent-to-treat analysis of the main efficacy criterion, namely ultrasonographic reduction of myoma(s) diameter, showed a significant difference in favour of leuprorelin (P=0.02) with a mean decrease of 26.5+/-4.5% (n=29) as opposed to 7.3+/-5% in the lynestrenol group (n=17). Clinical improvement was satisfactory in both groups. Hematocrit decrease between the preoperative value and the value measured 48 h postoperatively was significantly lower in the leuprorelin group than in the lynestrenol one (P=0.02) (for hemoglobin: P=0.07). CONCLUSION: Leuprorelin was more effective than lynestrenol because of its more intense antigonadotropic activity. The tolerance was good, reflecting each drug mechanism of action.

Avaliação da tolerabilidade e do controle de ciclo de dois contraceptivos orais de baixa dose: estudo comparativo aberto / Assessment of the tolerability and cycle control of two low-dose oral contraceptives: an open-label study

Realizou-se um estudo aberto comparativo em nove centros brasileiros para avaliar a tolerabilidade e o controle de ciclo obtido com o uso de dois contraceptivos orais de baixa dose contendo 20 mg etinilestradiol/75 mg gestodeno e 20 mg etinilestradiol/150 mg desogestrel, durante seis ciclos de tratamento. Foram selecionadas 167 mulheres saudáveis com vida sexual ativa (77 no grupo do gestodeno e 90 no grupo do desogestrel), das quais 138 completaram os seis ciclos de tratamento. Em um subgrupo de novas usuárias realizou-se também perfil lipídico e hemostático. Foram avaliados 867 diclos no total. Ocorreu sangramento irregular em 4,6 por cento dos ciclos com gestodeno e em 8,1 por cento com desogestrel. A tolerabilidade a ambas preparações foi boa, mas houve significativamente mais náusea no grupo do desogestrel. O controle de ciclo foi bom com os dois contraceptivos, sendo que houve freqüência significativamente menor de sangramento irregular no grupo do gestodeno quando se leva em conta que todos os ciclos foram considerados. Não houve alterações clinicamente significativas no perfil hemostático. O perfil lipídico mostrou tendência a tornar-se mais favorável após seis ciclos de tratamento com as duas preparações. Não ocorreu alteração no peso médio das mulheres no grupo do gestodeno; no grupo do desogestrel houve aumento significativo no peso médio de aproximadamente 1 Kg após seis meses de tratamento. A adesão ao tratamento foi boa com as duas preparações. Os resultados deste estudo mostram que preparações contendo baixa dose de gestodeno ou desogestrel associados a 20 mg de etinilestradiol são contraceptivos bem tolerados que permitem bom controle de ciclo, sem efeitos colaterais significantes.

[Coronary disease and hormonal treatment during the perimenopausal period]. / Choroba wiencowa a leczenie hormonalne w okresie okolomenopauzalnym.

Hormone replacement therapy (HRT) is widely recognized as probably most advisable treatment of perimenopausal women with cardiovascular disorders. Whenever HRT is administered for gynecological reasons, special attention should be paid to the presence of cardiological risk factors as these may be potentiated by high doses of gestogens. The authors undertake this problem inspired by a cases of a 53-years old patient (given oral lynestrol fair persisting uterine bleedings) who suffered from several complications, including venous thrombosis and myocardial infarction.

Fertility regulation in nursing women. IX. Contraceptive performance, duration of lactation, infant growth, and bleeding patterns during use of progesterone vaginal rings, progestin-only pills, Norplant implants, and Copper T 380-A intrauterine devices.

This study evaluated the performance of progesterone vaginal rings (n = 187), progestin-only pills (n = 117), Norplant implants (n = 120), and Copper T 380-A intrauterine devices (n = 122) in lactating women. Contraceptive efficacy, bleeding pattern, and influence of the method upon breastfeeding duration and infant growth were compared with those of untreated women (n = 236) who relied on lactational infertility. Participants were healthy, 18 to 38 years, had had a normal delivery, and were intending to breastfeed for as long as possible. Contraceptives were initiated at day 57 +/- 3 postpartum. Results are reported for the first year of use. All methods were highly effective, with pregnancy rates below 1%. None affected breastfeeding performance or the rate of infant growth. Users of the progestin-only methods experienced a period of lactational amenorrhea 4 to 5 months longer than did users of Copper T or untreated women. More than half of the women in each contraceptive group reported a bleeding in the first month after treatment initiation, which was not considered in the calculation of the duration of amenorrhea. Prolonged or frequent bleedings were infrequent. The proportion of bleedings lasting more than 10 days ranged from 0 in the progestin-only pills group to 7% in the Norplant implants group. The four methods, initiated around the eighth postpartum week, provided effective contraception with no negative effects upon lactation or infant growth and without the bleeding problems associated with their use in nonlactating women.

Cardiovascular risk factors in Norwegian women using oral contraceptives: results from a cardiovascular health screening 1985-88.

We analyzed data from 4,905 women aged 20-39 and 14,803 aged 40-49 who attended a health survey in Norway 1985-88, to study cardiovascular risk factors in users of oral contraceptives, all types and specifically by formulation. In age group 20-39, users of low-dose estrogen/ progestin regimens were younger, had lower body mass index (BMI), less often reported coronary heart disease in relatives, and less often used saturated fat on bread than did non-users. In age group 40-49, smoking was more prevalent in users of low-dose estrogen/progestin than in non-users. In both age groups the mean ratio of total/HDL cholesterol, the mean level of non-fasting triglycerides, and the mean systolic and diastolic blood pressures were higher in oral contraceptive users than in non-users. Among the users, a more favorable pattern was found in women using progestin-only oral contraceptives, as blood pressure levels were equal to those of non-users and total cholesterol and triglycerides were both 0.1-0.2 mmol/l below the non-users, in both age groups. However, users of low-dose estrogen formulations containing desogestrel 0.15 mg, norethisterone (norethindrone) 0.5 mg or lynestrenol 2.5 mg had the highest levels of HDL, even higher than the non-users. A pattern of higher triglycerides and higher ratio of total/ HDL cholesterol was found in smokers, compared with non-smokers, among users of any type of contraceptives, and in non-users.

[Enzyme therapy in treatment of mastopathy. A randomized double-blind clinical study]. / Enzymtherapie zur Behandlung der Mastopathie. Eine randomisierte doppelblinde klinische Studie.

In this randomized double-blind clinical study the efficacy of an enzyme preparation (Wobenzym) was compared with hormone therapy (Lynestrenol) in 29 women with mastopathy. There was a significantly greater decrease in number of hardenings of the mammary gland after 2 months of enzyme therapy than Lynestrenol therapy: improvement in the former group was 100%, in the latter group 78.6%. No significant difference was observed regarding the numbers of lumps, or number and size of cysts, sensitivity to touch, feeling of tension, spontaneous pain, and pain on pressure. The efficacy of both medicines is valued as good. Wobenzym therapy was tolerated very well. No side effects appeared at all. Enzyme therapy is an alternative, low-risk therapy for the management of mastopathy, which does not interfere with the already upset hormonal balance of the patients.

[Hormonal premedication in endometrium ablation--results of a prospective comparative study]. / Hormonale Vorbehandlung für die Endometriumablation--Ergebnisse einer prospektiven Vergleichsstudie.

In a prospective study in 40 patients the pretreatment for endometrial ablation with a gestagen (Orgametril 10 mg/die), danazol (600 mg/die) and an injection of a GnRH-analogon (Decapeptyl-Depot) was compared with a control group without pretreatment. The subjective estimation of the surgeon (endometrial thickness and depth of coagulation) showed a sufficient pretreatment in 90 % of all cases following danazol- and GnRH-analogon-pretreatment. In 90 % of the danazol- and GnRH-analogon pretreated group the histological findings showed also an atrophic or little proliferative endometrium. In a follow up of 6 months after endometrial ablation the highest amenorrhoea-rates were reached following danazol- and GnRH-analogon pretreatment. These two regimes should be used for the pretreatment for endometrial ablation.

[Megaloblastic changes in cervical epithelium associated with oral contraceptives and changes after treatment with folic acid].

OBJECTIVE: To study the influence of oral contraceptives on cervical epithelium, serum and red blood cell folate levels of users and to observe the changes after treatment with folic acid. METHODS: Morphology of cervical epithelium, serum folate and red blood cell folate levels were studied in 101 women who had used oral contraceptives for over 6 months and 33 intrauterine devices users served as controls, 29 women using oral contraceptives with cervical megaloblastic changes were treated with folic acid (5mg daily) for 3-4 weeks and followed up for observation on morphological changes of cervical epithelium. RESULTS: The mean nuclear diameter of cervical epithelial cells was larger in the oral contraceptive group than that in the control group (P < 0.001). Megaloblastic changes in cervical epithelium occurred in 29 women in the oral contraceptive group (28.7%). There was significant difference in the occurrence of cervical megaloblastic changes between the two groups (P < 0.01). The level of red blood cell folate was lower in the oral contraceptive group than that in the control group (P < 0.05). There was no difference in serum folate, hemoglobin and neutrophil nuclear index between the two groups (P > 0.05). The mean nuclear diameter of cervical epithelial cells decreased significantly (P < 0.001) and multinuclear and vacuolar changes disappeared after folic acid therapy in 26 women with megaloblastic changes. CONCLUSIONS: Oral contraceptives reduced folate storage in the body and resulted in megaloblastic changes in cervical epithelium. This condition was improved with folic acid therapy.

[Regression of functional cysts: high dosage ovulation inhibitor and gestagen therapy has no added effect]. / Zur Rückbildung funktioneller Zysten: Hochdosierte Ovulationshemmer und Gestagentherapie ohne zusätzlichen Effekt.

To investigate the need for hormonal treatment in patients with functional ovarian cysts (FOC), the efficacy of this treatment was evaluated in a retrospective and also in a randomised prospective study. By retrospective analyses the resolution of FOC with a mean diameter larger than 2.0 cm at the beginning of a cycle was determined in 113 patients (31.6 +/- 4.6 years). Fifty-seven women received an oral contraceptive (ethinylestradiol 50 micrograms/d for 7 days, ethinylestradiol 50 micrograms and desogestrel 125 micrograms/d for 15 days), the others had no therapy. In a second study 59 patients (32.3 +/- 4.6 years) were randomised to receive a combination of ethinylestradiol 50 micrograms and levonorgestrel 250 micrograms/d for 21 days (Group 1, n = 24), or lynestrenol 10 mg/d continuously (Group 2, n = 14) or a third group (Group 3, n = 21) without treatment. In both studies no differences were found between those patients who had hormonal treatment and those who had not. The prospective study revealed that spontaneously appearing FOC and FOC evolving after ovulation induction during the cycle prior to study enrolment, resolved equally well within 12 weeks independent of contraceptive or gestagen treatment. FOC persisted in only one woman (group 2) who had a surgically proven endometrioma. In conclusion, hormonal treatment does not produce regression of FOC in women of reproductive age.

Effects of a progestogen-only pill (Exluton) and an intrauterine device (Multiload Cu250) on breastfeeding.

The objective was to compare the effects of Exluton with those of Multiload Cu250, in an open-label, bi-center, randomized study in breastfeeding women. Subjects were randomized to one of the treatment groups 6 weeks after delivery. Women and their infants returned to the study site monthly and follow-up data regarding qualitative and quantitative characteristics of the breast milk, infant growth and infant and maternal health were obtained. There were no statistically significant differences between groups with regard to: (1) amount of milk drunk, amount of milk production, and number of daily breastfeedings; (2) mean milk concentrations of nutritional constituents (except higher milk levels of calcium and magnesium with Exluton during the first month); (3) infant anthropometric parameters. There were no between-group differences with regard to systolic or diastolic blood pressure. During the study, the mean maternal body weight in the Exluton group was significantly lower than in the Multiload Cu250 group. There were no differences between groups with regard to child or maternal health, except a lower incidence of child illness after 6 months in the Exluton group. This study confirms that both Exluton and Multiload Cu250 are acceptable and safe contraceptive methods in breastfeeding women.

Antiandrogen treatment with spironolactone and linestrenol decreases bone mineral density in eumenorrhoeic women with androgen excess.

Increased bone mineral density (BMD) has been reported in young women with androgen excess. To determine whether antiandrogen treatment in young women with androgen excess reduces BMD in these patients, the authors measured BMD before and a year after the beginning of antiandrogen therapy with spironolactone and linestrenol in 17 consecutive androgenized patients (median age 22 years). After a year's treatment BMD declined in 15 out of 17 patients, the mean decrease--0.032 g/cm2 (95% CI of the difference 0.016-0.048)--being highly significant (p < 0.001). Androstenedione decrease was the only hormonal variable significantly correlating with BMD decrease (r = 0.5; p = 0.037) according to simple linear regression. A decrease of BMD might become a key factor in deciding about the duration of antiandrogen treatment with spironolactone in functional hyperandrogenemia.

Gynecological problems of mentally retarded women. A case-control study from southern Finland.

Two hundred and fifty-five mentally retarded women (cases) and their age-matched control women with no mental retardation (controls) requiring the assistance of a gynecological consultant were studied. Reasons for consultation, heights, weights, blood pressures, smoking histories, medications, gynecological findings and therapeutic measures recommended after examination were recorded. In comparison to the group of non-mentally retarded control women the group of mentally retarded women had no deliveries at all, the number of pregnancies was 118.3 times less (p < 0.001), abortion 20 times less (p < 0.01), gynecological laparotomies 4.3 times less (p < 0.05) and diagnostic curettages 25.7 times less often (p < 0.001), but the number of lynestrenol induced therapeutic amenorrhea (TA) 123 times more (p < 0.001), anticonvulsive drug therapy 91 times more (p < 0.001), polypharmacy 22 times more (p < 0.01) and virginal gynecological status 11.7 times more often (p < 0.001). Further, among the mentally retarded cases than non-mentally retarded controls, contraception was 58 times less (p < 0.05), not smoking 1.2 times (p < 0.001), the incidence of genital infections 2.9 times and tumors of all kind 4.6 times less common (p < 0.001). Of the present mentally retarded women 67.5% had at least once in their life received lynestrenol for TA. Autopsy confirmed arterial diseases occurred in two out of four mentally retarded patients aged 44 and 45 years, who were current lynestrenol users and died during the study period. Therapeutic amenorrhea exhibited a clinical picture of depressed pituitary gonadal axis.