Int J Gynaecol Obstei 16: 124-127, 1978
Galactorrhea and the Defective Luteal Phase of the Menstrual Cycle S. EI Mahgoub Faculty of Medicine, Am Shams University, Cairo, Egypt
ABSTRACT El Mahgoub S (Faculty of Medicine, Ain Shams University, Cairo, Egypt). Galactorrhea and the defective luteal phase of the menstrual cycle. Int J Gynaecol Obstet 16: 124-127, 1978 Twelve patients with primary infertility due to a defective luteal phase associated with hyperprolactinemia and galactorrhea are reported. All were treated with 2-bromoergocryptine. During the first cycle of therapy, the serum prolactin level decreased in all cases, and galactorrhea disappeared during the second cycle of therapy. Seven women responded to 2-bromoergocryptine, as was reflected in their endometrial biopsies. The remaining five were given clomiphene citrate on the second and sixth days of the next 2-bromoergocryptine cycle. Three of these patients responded favorably to this combined therapy. Six pregnancies were reported during therapy. The results of follow-up after labor or abortion suggested that these cases represent a latent stage of the amenorrhea-galactorrhea syndrome.
INTRODUCTION T h e defective luteal phase is recognized as an etiologic factor in infertility. T h e incidence of this condition among infertile women has been reported as varying between 3.5% and 19.0% (3, 6, 8, 9). In our own population, it is a contributing factor in approximately 4.5% of the cases of infertility (5). T h e pathogenesis of a corpus luteum defect may encompass a multitude of etiologies. It may result from insufficient gonadotropic stimulation, metabolic disturbances or premature decay of the corpus luteum. A few current reports indicate a possible association of luteal phase defects and elevated serum prolactin levels in women (4, 12, 15). At present the data are still too preliminary to document a specific role for prolactin in ovarian function. We report here 12 cases of primary infertility due to a defective luteal phase associated with hyperpro-
Int J Gynaecol Obstet 16
lactinemia and galactorrhea and illustrate the therapeutic response to an ergot alkaloid bromo-2-ergocriptine (Bromergocryptine CB-154, AG Sandoz, Basel, Switzerland) or a combination of 2-bromoergocryptine and clomiphene citrate.
MATERIALS A N D M E T H O D S The 12 patients in this series attended our clinic for evaluation and treatment of primary infertility. All of them had mild galactorrhea, in which a milky fluid could be obtained after manual expression. During routine questioning, ten of the women gave a history of galactorrhea, but the remaining two were unaware of its presence, making assessment of its duration difficult. The group ranged in age from 25 to 40 years, and their infertility had extended from 3 to 16 years. Examination indicated that a defective luteal phase was the sole factor responsible for the primary infertility in ten of the patients. Unilateral tubal cornual block was encountered in one woman and mild oligospermia in the husband of another. Two diagnoses each of hypothyroidism and cystic ovaries were established. T h e significant clinical data are presented in Table I. Tomography of the sella turcica and visual field examination revealed no abnormalities.
Diagnostic procedures Luteal defects were established through histologic dating of the premenstrual endometrial biopsy, which was timed with basal body temperature (BBT) charts. Biopsies were obtained two days before the expected onset of menstruation for two consecutive months. The specimens were dated according to the criteria of Noyes et al (13). Two baseline radioimmunoassay determinations of serum prolactin were obtained (2).
Galactorrhea and 2-bromoergocryptine 125
Table I. Clinical findings among 12 infertile women with galactorrhea. Case Number 1 2 3 4 5 6 7 8 9 10 11 12
Age (years) 38 40 25 28 37 37 37 32 27 27 27 37
Height (cm) 162 156 153 158 169 160 161 166 156 151 153 173
Weight (kg) 72 81 85 53 66 61 53 80 60 58 54 68
Length of Menstrual Cycle (days) 33-45° 26 30-45° 26-39° 30 26 28 25 24 28 28 25
Duration (years) Infertility 15 8 4 3 9 12 7 11 5 6 4 16
Galactorrhea 8 5 3 3 4 8 3 ? ?
3 2 6
" Rhythm of menstrual cycle was irregular.
Previous therapy All of the patients had been treated by at least one of a number of therapeutic modalities before being included in the present trial. Progesterone had been prescribed in every case, for a period of three months, except for two women who took it for six months. Clomiphene had been administered for three months to ten of the 12 patients. Five women had taken gonadotropins for three or six months, two had been on thyroxine or antithyroid medication for six months, and two others had been using contraceptive pills for six months. Treatment and follow-up Treatment was started on the first day of menstruation with a dose of 2.5 mg of 2-bromoergocryptine twice daily with meals. Progress was monitored by recording the BBT, observing the galactorrhea, estimating the serum prolactin and dating the premenstrual endometrial biopsies. T h e serum prolactin and endometrial biopsies were examined two days before the expected onset of menses (average, 26th day of the first cycle). If the endometrium still revealed abnormal dating, clomiphene citrate (100 mg daily from the second to the sixth days of cycle) was given in addition to the 2-bromoergocryptine. The endometrial biopsy was subsequently repeated to investigate the effect of this combined therapy. RESULTS Serum prolactin and galactorrhea During the first cycle of therapy, the serum prolactin level decreased markedly in all cases. Milk
expression stopped completely during the second cycle (Table II). Endometrial biopsy During the first cycle of therapy, seven women revealed a normal endometrial pattern which agreed with the estimated date of ovulation, according to the BBT charts. Combined 2-bromoergocryptine and clomiphene citrate therapy was given to the remaining five patients who had failed to respond to the first drug alone. T h e results were favorable in three of these cases. Pregnancy Six pregnancies were reported during therapy. It is notable that three of these patients developed persistent amenorrhea and copious galactorrhea after labor or abortion, and a fourth developed galactorrhea only. T h e remaining two women are currently pregnant.
DISCUSSION The present investigation documents the contention that hyperprolactinemia and galactorrhea may be associated with a defective luteal phase. Whether prolactin hypersecretion acts at the hypothalamicpituitary level to decrease gonadotropin secretion or at an ovarian level to decrease progesterone, or both, remains to be established. Luteal defects may result from inadequate follicle-stimulating hormone (FSH) (16), luteinizing hormone (LH) surge (18) or residual tonic L H (17).
IntJ Gynaecol Obstet 16
126
ElMahgoub
Table II. Serum prolactin levels before and after treatment and after pregnancy. Serumi Prolactin Level (ng/ml)" in Cases 2
3
4
5
6
7
46 18 103
38 20
58 23 68
44 13 69
66 16
106 28
54 10 73
CM CM
Before treatment After treatment After pregnancy6
1
8
9
10
11
12
ooo
Time Period
49 31
86 21
41 16
102 23
" Normal serum prolactin level = 20 ng/ml. " Six women became pregnant; two were still pregnant at termination of the study.
Increased prolactin secretion is due to a decrease in the hypothalamic prolactin-inhibiting factor (PIF). A dysfunction in the hypothalamus that results in a decreased PIF synthesis could secondarily alter normal hypothalamic synthesis or secretion of gonadotropin-releasing hormone and, consequently, pituitary FSH or L H secretion. T h e presence of elevated levels of prolactin may be responsible for the refractoriness of the ovaries to gonadotropins (18, 19). T h e addition of prolactin to the media of h u m a n granulosa cells cultured in vitro results in a decreased progesterone synthesis (11). However, the results of other investigators (1) do not support the concept that prolactin has an inhibitory effect on ovarian levels. It is remarkable that progesterone substitution therapy failed to induce pregnancy in these cases of hyperprolactinemia. This may be the result of an associated relative estrogen deficiency. Sengupta (14) found that 80% of patients with a defective luteal phase had a relative or marked estrogen deficiency. T h e failure of clomiphene citrate or gonadotropins to induce pregnancy in such cases may denote refractoriness of the ovaries in the presence of hyperprolactinemia. Prolactin suppression with 2-bromoergocryptine was associated with restoration of a normal luteal phase in seven of the study group (58%). This result documents the concept that hyperprolactinemia may have a definite role in the etiology of luteal defects. Further, addition of clomiphene citrate to 2-bromoergocryptine succeeded in correcting luteal defects in three other women. This may be the result of an augmented responsiveness of pituitary gonadotropins. Hirvone et al (7) found that in cases of secondary amenorrhea prolactin suppression was associated with the restoration of clomiphene responsiveness. It is believed that, depending on the extent of the defect or the stage of the disease, a patient may show evidence of either luteal phase defects or persistent amenorrhea. O u r results indicate that these
IntJ Gynaecol Obstet 16
are potential cases of the amenorrhea-galactorrhea syndrome. Pregnancy is the main determinant of the development of this condition. After their first pregnancy, three of the women developed the full galactorrhea-amenorrhea syndrome and the fourth developed copious galactorrhea. In all of them, the serum prolactin level was markedly raised. These findings suggest that the presence of a defective luteal phase demands a search for galactorrhea. Levels of prolactin in these patients a n d in those without evident galactorrhea should be estimated for detection of hyperprolactinemia.
ACKNOWLEDGMENT I wish to thank Dr S. Kadry, professor of gynecologic pathology, for reading and dating the endometrial biopsies.
REFERENCES 1. Acher DF, Josimovich J B : Ovarian response to exogenous gonadotrophins in women with elevated serum prolactin. Obstet Gynecol 48:155, 1976. 2. Aubert M L , G r u m b a c h M M , Kaplan SL: Heterologous radioimmunoassay for plasma h u m a n prolactin (hPRL) values in normal subjects, puberty, pregnancy a n d in pituitary disorders. Acta Endocrinol (Kbh) 77:460, 1974. 3. Botella-Llusía J: Endocrinology of Women (trans EA Moscovic). WB Saunders Co, Philadelphia, 1973. 4. Corneblum B, Pairaudeau N, Shewchuk A: Prolactin hypersecretion and short luteal phase defects. Obstet Gynecol 74A, 1975. 5. El Mahgoub S: Defective luteal phase. Ain Shams M e d J (in press). 6. Gillam J S : Study of inadequate secretion phase of endometrium. Fértil Steril fj: 18, 1955. 7. Hirvone E, Rant AT, Seppal A M : Prolactin suppression stimulates clomiphene responsiveness. Int J Fértil 21A, 1976. 8. Israel SL: Diagnosis and Treatment of Menstrual Disorders and Sterility, 5th ed. Hoeber Medical Division, H a r p e r & Row, New York, 1967.
Galactorrhea and 2-bromoergocryptine 127
9. Jones GS: T h e luteal phase defects. Fértil Steril 27:4, 1976. 10. Jones GS, Madrigal-Castro V: Hormonal findings in association with abnormal corpus luteum function in humans: the luteal phase defects. Fértil Steril 2 / . 1 , 1970. 11. M c N a t t y K P , H u n t e r W M , McNeilly AS, Sawyers R S : Changes in the concentration of the pituitary and steroid hormones in the follicular fluid of h u m a n Graafian follicles throughout the menstrual cycle. J Endocrinol (Kbh) 64:555, 1975. 12. M c N a t t y K P , Sawyers RS, McNeilly A: A possible role for prolactin in control of steroid secretion by the h u m a n Graafian follicle. N a t u r e 250:653, 1974. 13. Noyes R W , Hertig A, Rock J : Dating the endometrial biopsies. Fértil Steril / : 3 , 1950. 14. Sengupta BS: Defective luteal phase—measurement and evaluation of ovarian hormone before and during cyclofenil (Bis-P-Acetoxyphenyl) cyclohexylidenemethane (Compound 6066) treatment. West Indian Med J 25:107, 1976. 15. Sépala M, Hirvonen E, R a n t a R: Hyperprolactinemia and luteal insufficiency. Lancet /:229, 1976. 16. Strot CA, Gargille C M , Ross G T , Lipsett M R : T h e short luteal phase. J Clin Endocrinol M e t a b 30:246, 1970.
17. V a n de Weile R L , Boguml J , Dyrenfurth I, Ferin M, Jewelewicz X, Warren M, Rizkallah J , Mikhail G: Mechanism regulating the menstrual cycle in women recentlypregnant. Horm Res 26:36, 1970. 18. Zarate A, Canales ES, Soria J , Léon C, Garrido J , Fonseca E: Refractory postpartum ovarian response to gonadal stimulation in nonlactating women. Obstet Gynecol ^4:819, 1974. 19. Zarate A, Canales ES, Soria J , Ruiz F, MacGregor C: Ovarian refractoriness during lactation in women: effect of gonadotropin stimulation. Am J Obstet Gynecol 112:\ 130, 1972.
Address for reprints: S. El Mahgoub Faculty of Medicine Ain Shams University Cairo Egypt
InlJ Gynaecol Obstet 16
Galactorrhea and the Defective Luteal Phase of the Menstrual Cycle S. EI Mahgoub Faculty of Medicine, Am Shams University, Cairo, Egypt
ABSTRACT El Mahgoub S (Faculty of Medicine, Ain Shams University, Cairo, Egypt). Galactorrhea and the defective luteal phase of the menstrual cycle. Int J Gynaecol Obstet 16: 124-127, 1978 Twelve patients with primary infertility due to a defective luteal phase associated with hyperprolactinemia and galactorrhea are reported. All were treated with 2-bromoergocryptine. During the first cycle of therapy, the serum prolactin level decreased in all cases, and galactorrhea disappeared during the second cycle of therapy. Seven women responded to 2-bromoergocryptine, as was reflected in their endometrial biopsies. The remaining five were given clomiphene citrate on the second and sixth days of the next 2-bromoergocryptine cycle. Three of these patients responded favorably to this combined therapy. Six pregnancies were reported during therapy. The results of follow-up after labor or abortion suggested that these cases represent a latent stage of the amenorrhea-galactorrhea syndrome.
INTRODUCTION T h e defective luteal phase is recognized as an etiologic factor in infertility. T h e incidence of this condition among infertile women has been reported as varying between 3.5% and 19.0% (3, 6, 8, 9). In our own population, it is a contributing factor in approximately 4.5% of the cases of infertility (5). T h e pathogenesis of a corpus luteum defect may encompass a multitude of etiologies. It may result from insufficient gonadotropic stimulation, metabolic disturbances or premature decay of the corpus luteum. A few current reports indicate a possible association of luteal phase defects and elevated serum prolactin levels in women (4, 12, 15). At present the data are still too preliminary to document a specific role for prolactin in ovarian function. We report here 12 cases of primary infertility due to a defective luteal phase associated with hyperpro-
Int J Gynaecol Obstet 16
lactinemia and galactorrhea and illustrate the therapeutic response to an ergot alkaloid bromo-2-ergocriptine (Bromergocryptine CB-154, AG Sandoz, Basel, Switzerland) or a combination of 2-bromoergocryptine and clomiphene citrate.
MATERIALS A N D M E T H O D S The 12 patients in this series attended our clinic for evaluation and treatment of primary infertility. All of them had mild galactorrhea, in which a milky fluid could be obtained after manual expression. During routine questioning, ten of the women gave a history of galactorrhea, but the remaining two were unaware of its presence, making assessment of its duration difficult. The group ranged in age from 25 to 40 years, and their infertility had extended from 3 to 16 years. Examination indicated that a defective luteal phase was the sole factor responsible for the primary infertility in ten of the patients. Unilateral tubal cornual block was encountered in one woman and mild oligospermia in the husband of another. Two diagnoses each of hypothyroidism and cystic ovaries were established. T h e significant clinical data are presented in Table I. Tomography of the sella turcica and visual field examination revealed no abnormalities.
Diagnostic procedures Luteal defects were established through histologic dating of the premenstrual endometrial biopsy, which was timed with basal body temperature (BBT) charts. Biopsies were obtained two days before the expected onset of menstruation for two consecutive months. The specimens were dated according to the criteria of Noyes et al (13). Two baseline radioimmunoassay determinations of serum prolactin were obtained (2).
Galactorrhea and 2-bromoergocryptine 125
Table I. Clinical findings among 12 infertile women with galactorrhea. Case Number 1 2 3 4 5 6 7 8 9 10 11 12
Age (years) 38 40 25 28 37 37 37 32 27 27 27 37
Height (cm) 162 156 153 158 169 160 161 166 156 151 153 173
Weight (kg) 72 81 85 53 66 61 53 80 60 58 54 68
Length of Menstrual Cycle (days) 33-45° 26 30-45° 26-39° 30 26 28 25 24 28 28 25
Duration (years) Infertility 15 8 4 3 9 12 7 11 5 6 4 16
Galactorrhea 8 5 3 3 4 8 3 ? ?
3 2 6
" Rhythm of menstrual cycle was irregular.
Previous therapy All of the patients had been treated by at least one of a number of therapeutic modalities before being included in the present trial. Progesterone had been prescribed in every case, for a period of three months, except for two women who took it for six months. Clomiphene had been administered for three months to ten of the 12 patients. Five women had taken gonadotropins for three or six months, two had been on thyroxine or antithyroid medication for six months, and two others had been using contraceptive pills for six months. Treatment and follow-up Treatment was started on the first day of menstruation with a dose of 2.5 mg of 2-bromoergocryptine twice daily with meals. Progress was monitored by recording the BBT, observing the galactorrhea, estimating the serum prolactin and dating the premenstrual endometrial biopsies. T h e serum prolactin and endometrial biopsies were examined two days before the expected onset of menses (average, 26th day of the first cycle). If the endometrium still revealed abnormal dating, clomiphene citrate (100 mg daily from the second to the sixth days of cycle) was given in addition to the 2-bromoergocryptine. The endometrial biopsy was subsequently repeated to investigate the effect of this combined therapy. RESULTS Serum prolactin and galactorrhea During the first cycle of therapy, the serum prolactin level decreased markedly in all cases. Milk
expression stopped completely during the second cycle (Table II). Endometrial biopsy During the first cycle of therapy, seven women revealed a normal endometrial pattern which agreed with the estimated date of ovulation, according to the BBT charts. Combined 2-bromoergocryptine and clomiphene citrate therapy was given to the remaining five patients who had failed to respond to the first drug alone. T h e results were favorable in three of these cases. Pregnancy Six pregnancies were reported during therapy. It is notable that three of these patients developed persistent amenorrhea and copious galactorrhea after labor or abortion, and a fourth developed galactorrhea only. T h e remaining two women are currently pregnant.
DISCUSSION The present investigation documents the contention that hyperprolactinemia and galactorrhea may be associated with a defective luteal phase. Whether prolactin hypersecretion acts at the hypothalamicpituitary level to decrease gonadotropin secretion or at an ovarian level to decrease progesterone, or both, remains to be established. Luteal defects may result from inadequate follicle-stimulating hormone (FSH) (16), luteinizing hormone (LH) surge (18) or residual tonic L H (17).
IntJ Gynaecol Obstet 16
126
ElMahgoub
Table II. Serum prolactin levels before and after treatment and after pregnancy. Serumi Prolactin Level (ng/ml)" in Cases 2
3
4
5
6
7
46 18 103
38 20
58 23 68
44 13 69
66 16
106 28
54 10 73
CM CM
Before treatment After treatment After pregnancy6
1
8
9
10
11
12
ooo
Time Period
49 31
86 21
41 16
102 23
" Normal serum prolactin level = 20 ng/ml. " Six women became pregnant; two were still pregnant at termination of the study.
Increased prolactin secretion is due to a decrease in the hypothalamic prolactin-inhibiting factor (PIF). A dysfunction in the hypothalamus that results in a decreased PIF synthesis could secondarily alter normal hypothalamic synthesis or secretion of gonadotropin-releasing hormone and, consequently, pituitary FSH or L H secretion. T h e presence of elevated levels of prolactin may be responsible for the refractoriness of the ovaries to gonadotropins (18, 19). T h e addition of prolactin to the media of h u m a n granulosa cells cultured in vitro results in a decreased progesterone synthesis (11). However, the results of other investigators (1) do not support the concept that prolactin has an inhibitory effect on ovarian levels. It is remarkable that progesterone substitution therapy failed to induce pregnancy in these cases of hyperprolactinemia. This may be the result of an associated relative estrogen deficiency. Sengupta (14) found that 80% of patients with a defective luteal phase had a relative or marked estrogen deficiency. T h e failure of clomiphene citrate or gonadotropins to induce pregnancy in such cases may denote refractoriness of the ovaries in the presence of hyperprolactinemia. Prolactin suppression with 2-bromoergocryptine was associated with restoration of a normal luteal phase in seven of the study group (58%). This result documents the concept that hyperprolactinemia may have a definite role in the etiology of luteal defects. Further, addition of clomiphene citrate to 2-bromoergocryptine succeeded in correcting luteal defects in three other women. This may be the result of an augmented responsiveness of pituitary gonadotropins. Hirvone et al (7) found that in cases of secondary amenorrhea prolactin suppression was associated with the restoration of clomiphene responsiveness. It is believed that, depending on the extent of the defect or the stage of the disease, a patient may show evidence of either luteal phase defects or persistent amenorrhea. O u r results indicate that these
IntJ Gynaecol Obstet 16
are potential cases of the amenorrhea-galactorrhea syndrome. Pregnancy is the main determinant of the development of this condition. After their first pregnancy, three of the women developed the full galactorrhea-amenorrhea syndrome and the fourth developed copious galactorrhea. In all of them, the serum prolactin level was markedly raised. These findings suggest that the presence of a defective luteal phase demands a search for galactorrhea. Levels of prolactin in these patients a n d in those without evident galactorrhea should be estimated for detection of hyperprolactinemia.
ACKNOWLEDGMENT I wish to thank Dr S. Kadry, professor of gynecologic pathology, for reading and dating the endometrial biopsies.
REFERENCES 1. Acher DF, Josimovich J B : Ovarian response to exogenous gonadotrophins in women with elevated serum prolactin. Obstet Gynecol 48:155, 1976. 2. Aubert M L , G r u m b a c h M M , Kaplan SL: Heterologous radioimmunoassay for plasma h u m a n prolactin (hPRL) values in normal subjects, puberty, pregnancy a n d in pituitary disorders. Acta Endocrinol (Kbh) 77:460, 1974. 3. Botella-Llusía J: Endocrinology of Women (trans EA Moscovic). WB Saunders Co, Philadelphia, 1973. 4. Corneblum B, Pairaudeau N, Shewchuk A: Prolactin hypersecretion and short luteal phase defects. Obstet Gynecol 74A, 1975. 5. El Mahgoub S: Defective luteal phase. Ain Shams M e d J (in press). 6. Gillam J S : Study of inadequate secretion phase of endometrium. Fértil Steril fj: 18, 1955. 7. Hirvone E, Rant AT, Seppal A M : Prolactin suppression stimulates clomiphene responsiveness. Int J Fértil 21A, 1976. 8. Israel SL: Diagnosis and Treatment of Menstrual Disorders and Sterility, 5th ed. Hoeber Medical Division, H a r p e r & Row, New York, 1967.
Galactorrhea and 2-bromoergocryptine 127
9. Jones GS: T h e luteal phase defects. Fértil Steril 27:4, 1976. 10. Jones GS, Madrigal-Castro V: Hormonal findings in association with abnormal corpus luteum function in humans: the luteal phase defects. Fértil Steril 2 / . 1 , 1970. 11. M c N a t t y K P , H u n t e r W M , McNeilly AS, Sawyers R S : Changes in the concentration of the pituitary and steroid hormones in the follicular fluid of h u m a n Graafian follicles throughout the menstrual cycle. J Endocrinol (Kbh) 64:555, 1975. 12. M c N a t t y K P , Sawyers RS, McNeilly A: A possible role for prolactin in control of steroid secretion by the h u m a n Graafian follicle. N a t u r e 250:653, 1974. 13. Noyes R W , Hertig A, Rock J : Dating the endometrial biopsies. Fértil Steril / : 3 , 1950. 14. Sengupta BS: Defective luteal phase—measurement and evaluation of ovarian hormone before and during cyclofenil (Bis-P-Acetoxyphenyl) cyclohexylidenemethane (Compound 6066) treatment. West Indian Med J 25:107, 1976. 15. Sépala M, Hirvonen E, R a n t a R: Hyperprolactinemia and luteal insufficiency. Lancet /:229, 1976. 16. Strot CA, Gargille C M , Ross G T , Lipsett M R : T h e short luteal phase. J Clin Endocrinol M e t a b 30:246, 1970.
17. V a n de Weile R L , Boguml J , Dyrenfurth I, Ferin M, Jewelewicz X, Warren M, Rizkallah J , Mikhail G: Mechanism regulating the menstrual cycle in women recentlypregnant. Horm Res 26:36, 1970. 18. Zarate A, Canales ES, Soria J , Léon C, Garrido J , Fonseca E: Refractory postpartum ovarian response to gonadal stimulation in nonlactating women. Obstet Gynecol ^4:819, 1974. 19. Zarate A, Canales ES, Soria J , Ruiz F, MacGregor C: Ovarian refractoriness during lactation in women: effect of gonadotropin stimulation. Am J Obstet Gynecol 112:\ 130, 1972.
Address for reprints: S. El Mahgoub Faculty of Medicine Ain Shams University Cairo Egypt
InlJ Gynaecol Obstet 16
