Follicle luteinization in hyperandrogenic follicles of polycystic ovary syndrome patients undergoing gonadotropin therapy for in vitro fertilization

CONTEXT: Polycystic ovary syndrome (PCOS) is a reproductive disorder of ovarian hyperandrogenism and insulin resistance characterized by abnormal luteinization of small follicles. After exposure to GnRH analog/FSH stimulation for in vitro fertilization (IVF), however, it is unclear whether such PCOS follicles remain abnormally luteinized during the resumption of oocyte maturation in vivo. OBJECTIVE: The aim of this study was to determine whether PCOS follicles exposed to GnRH analog/FSH stimulation for IVF show abnormal luteinization. DESIGN: This study was a prospective cohort. SETTING: The setting was an institutional practice. Patients: Eleven PCOS and 30 normoandrogenic ovulatory women were included. INTERVENTION(S): All subjects received GnRH analog/FSH therapy after basal serum hormone determinations. MAIN OUTCOME MEASURE(S): Follicle fluid aspirated at oocyte retrieval from the first follicle of each ovary was assayed for gonadotropins, steroids, insulin, and glucose. LH receptor mRNA expression was determined in granulosa cells of the same follicle. RESULTS: In PCOS patients with basal hyperandrogenemia and hyperinsulinemia, total oocyte number was increased and follicle diameter was decreased, despite normal maximal serum estradiol levels. Within PCOS follicles, progesterone levels were reduced (P < 0.01), despite comparable bioactive LH and insulin levels and granulosa cell LH receptor mRNA expression; estradiol levels were normal, despite diminished FSH availability (P < 0.004). Elevated androstenedione (P < 0.01), testosterone (P < 0.001), and glucose (P < 0.01) levels also occurred. In PCOS follicles containing mature oocytes, however, elevated androgen levels were accompanied by both normal progesterone concentrations and a normal inverse relationship between glucose depletion and lactate accumulation. CONCLUSION: Hyperandrogenic follicles with mature oocytes from PCOS women receiving GnRH analog/recombinant human FSH therapy for IVF show sufficient glucose utilization for normal luteinization.     

Studies of the role of sex steroids in the feedback control of FSH concentrations in men

Studies on the role of sex steroids in the feedback control of follicle stimulating hormone (FSH) concentrations in 22-35 year old men are reported. 10 normal volunteers and 8 men undergoing evaluation for azoospermia or oligospermia received steroids by constant infusion for 96 hours at twice the estimated daily production rate of normal men to obtain stable levels in peripheral blood. 15 mg of testosterone increased plasma testosterone and estradiol levels 2-fold and suppressed FSH and luteinizing hormone (LH) approximately 40% during infusion Days 3 and 4. 90 mcg of estradiol/day caused similar suppression of FSH and LH and the addition of 4.5 mg of 17 alpha-hydroxyprogesterone had no additive effect. 7.5 mg of dihydrotestosterone/day produced no detectible changes in FSH or LH. No evidence for a selective effect of any of the steroids on FSH secretion was seen. These data support the concept that although there is a specific seminiferous tubular factor regulating FSH secretion, testicular steroids also modulate FSH secretion.     

The menopausal transition: analysis of LH, FSH, estradiol, and progesterone concentrations during menstrual cycles of older women.

Studies of menstrual cycle length in large populations demonstrated that there is a striking increase in the variability of intermenstrual intervals just before menopause. The changes in serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), and progesterone (P) during menstrual cycles in a group of perimenopausal women were compared with the findings in young normal women. In 8 women, 46-56 years old with regular cycles, cycle length was shorter and the mean E2 concentration was lower than in younger women. There was a striking increase in FSH concentration throughout the cycle while LH remained in the normal range. In 2 women, 14 cycles of variable length were studied during 2 years of the menopausal transition. In some instances, hormonal changes associated with follicular maturation and corpus luteum function occurred in the presence of high, menopausal levels of LH and FSH with a diminished secretion of E2 and P. In others vaginal bleeding occurred during a fall in serum E2 with no associated rise in P. Cycles of variable length during the menopausal transition may be due either to irregular maturation of residual follicles with diminished responsiveness to gonadotropin stimulation, or to anovulatory vaginal bleeding that may follow estrogen withdrawal without evidence of corpus luteum function. The observation of elevated FSH concentrations and normal LH levels in perimenopausal women emphasizes the complexity of the hypothalamic-pituitary-ovarian regulatory system and suggests that LH and FSH are modulated independently at the level of the pituitary.     

Experimental studies on the endocrine regulations during the periovulatory phase of the human menstrual cycle. The effects of exogenous 17 -oestradiol and progesterone on the release of pituitary luteinizing and follicle stimulating hormones

In order to simulate some parts of the progesterone and estrogen patterns of the normal menstrual cycle in a normal women, im injections of progesterone and estradiol benzoate were used in 7 amenorrheic, castrated, postmenopausal, or eugonadal women who were receiving 60 mcg of ethinyl estradiol orally per day. Both progesterone and estradiol benzoate were found to produce a positive feedback on the hypothalamic cycle center as measured by the plasma LH surge. Subsequent LH peaks could be induced by either hormone after an estradiol-induced peak, but neither hormone could induce an LH peak after the first progesterone-induced peak. Progesterone-induced LH peaks were always immediate and short-lived with the duration of the LH release appearing to be inversely related to the dose. Estradiol-induced LH peaks did not appear until at least 24 hours after the injection. Only progesterone induced a significant increase in plasma FSH levels. It is inferred from these experiments and the steroid pattern of the normal mentrual cycle that 17-beta-estradiol is the initial triggering stimulus in the cycle leading to an LH surge. This in turn results in an increase in plasma progesterone which regulates the amount of LH release in the second part of the biphasic midcycle peak, which is a possible periovulatory mechanism for mono-ovulation in the human female.     

Testicular function after radioiodine therapy in patients with thyroid cancer.

Our aim was to assess testicular function in patients treated with high-dose radioiodine. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels were determined in 52 men with thyroid carcinoma before and 6, 12, and 18 months after radioiodine therapy (3.7-5.5 GBq (131)I; mean, 4.25 GBq (131)I) (group 1) and were also determined before and 18 months after the last radioiodine therapy in 22 patients who received high cumulative activities (13-27.7 GBq; mean, 20.3 GBq (131)I) (group 2). FSH levels were increased 6 months after therapy in all patients of group 1, while a decline was observed after 12 months, with 37 of 52 (71%) subjects presenting normal values. FSH values returned to normal after 18 months in all patients. In group 2, 12 of 22 (54.5%) patients presented elevated FSH and 8 (66%) of these individuals had oligospermia. Six months after radioiodine, increased LH levels were observed in only 5 of 52 (9.6%) patients of group 1, which returned to normal after 12 months, and in 5 of 22 (22%) of group 2. All patients showed normal testosterone levels. We conclude that 131I therapy may cause impairment of testicular function. A generally transient increase in FSH is highly common but is usually reversed within 18 months. Oligospermia was common (one third) after high cumulative (131)I activities. Becausee we did not perform a spermiogram before therapy, we cannot state that high cumulative (131)I activities cause permanent infertility. We recommend the routine use of sperm banks in the cases of men who still wish to have children and who will undergo therapy with (131)I activities of 14 GBq or more or in the case of patients with pelvic metastases.     

Progesterone induced modulations of serum hormonal profiles in adult male and female rats.

The impact of progesterone on serum hormonal profiles in the presence and absence of gonads was studied in adult male and female albino rats. Progesterone was administered intramuscularly for 30 days at a dose of 1 mg/100g body weight/day. Serum testosterone, estradiol and prolactin titres decreased in male and female rats with intact gonads given progesterone. While the levels of both luteinizing hormone (LH) and follicle stimulating hormone (FSH) decreased in male rats with intact gonads, only FSH decreased in female rats. The inhibitory effect of progesterone on serum estradiol, LH, FSH and prolactin persisted even after gonadectomy in male rats. This persistent inhibitory effect of progesterone was also seen on serum testosterone, FSH and prolactin levels of female rats. Ovariectomy modified progesterone action on LH, as is evident from the decreased levels of LH observed only in ovariectomized rats given progesterone. While progesterone had no effect on serum T3 and T4 in male rats, gonadectomy altered the levels of T3 and T4 in male and female rats. Progesterone increased the levels of T3 and decreased the levels of T4 in ovariectomized rats. Growth hormone (GH) and thyroid stimulating hormone (TSH) levels seem to be resistant to changes in progesterone titre, irrespective of the sex and gonadal status. The present data suggest the existence of a sex specific effect of progesterone on gonadotrophins. The data on T3, T4 and TSH reveals that progesterone has no effect on the pituitary thyroid axis in the presence of gonads.     

The pituitary-gonadal axis in women with benign or malignant ovarian tumors.

The serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), human chorionic gonadotropin (hCG), estradiol, progesterone, androstenedione, testosterone (total and free) and dehydroepiandrosterone sulphate (DHEAS) were investigated prior to surgery in 24 postmenopausal women with benign and 28 postmenopausal women with malignant epithelial ovarian tumors. The serum concentrations of hormones were compared with those of 28 healthy, postmenopausal, age-matched controls. Significantly lower serum FSH levels were demonstrated in women with malignant tumors. No significant differences were found between the groups regarding the serum LH levels. The hCG levels were low in all groups. Regarding progesterone and estradiol levels, low postmenopausal steroid levels were found in all groups examined and no significant differences were demonstrated within the groups. No significant correlations between the levels of estradiol and FSH or progesterone and LH were demonstrated. To exclude a central depression of gonadotropin release mediated by the dopaminergic system we examined the thyroid stimulating hormone (TSH) and prolactin. No differences were found between the groups regarding TSH and prolactin levels. A possible relationship between other hormones/factors produced by the tumor and exerting a negative feedback, either centrally or directly, on the gonadotropin release remains to be investigated. A change in biological activity in the gonadotropins might explain the present findings.     

Reproductive and endocrine gonadal capacity in patients treated with COPP chemotherapy for Hodgkin's disease

Summary Testicular and ovarian functions were assessed in 33 patients with Hodgkin's disease 1 to 17 years after cessation of COPP chemotherapy with cyclophosphamide, vincristine, procarbazine, prednisone. Diagnostic procedures consisted of hormone measurements, interviews, and semen analyses. In women serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17-estradiol, progesterone, prolactin, and in men FSH, LH, 17-estradiol, testosterone, and prolactin were determined. Semen analyses were performed in all men. Information concerning pregnancies, pregnancy outcome, future fertility wishes, sexual functions, menstrual pattern, and incidence of premature menopausal symptoms was ascertained by interview and questionnaire. Nineteen of 19 (100%) men showed elevated serum FSH levels between 715 and 1910 (median 1095) ng/ml and azoospermia, 1 to 11 years afters therapy. Serum levels of testosterone were within normal limits in 18/19 (95%) of the men, and LH values were normal in all men. Permanent ovarian failure occurred in 8/14 (57%) women, causing infertility and premature menopausal symptoms. The incidence of ovarian failure in women over 24 years was 86% (6/7) versus 28% (2/7) in those under 24 years at the time of treatment. In women receiving estrogen replacement, incidence and severity of these symptoms were significantly reduced. Of 14 women 3(21%) became pregnant and delivered 5 healthy children after treatment. Our results suggest irreversible sterility and normal Leydig cell function after COPP chemotherapy in all men. Druginduced ovarian failure was age-related and caused premature menopausal symptoms, detracting from the quality of the patient's life. To reduce premature menopausal symptoms and to prevent adverse cardiovascular and metabolic late sequelae, hormonal replacement is indicated. Pregnancies ending in normal live births can be achieved after COPP chemotherapy in young women. In both men and women, serum FSH and LH levels proved to be feasible markers to determine degree and duration of endocrine and reproductive gonadal injury after chemotherapy.Supported in part by a grant from Deutsche Krebshilfe (M16/86 He 3)     

Roles of estradiol and progesterone in eiliciting the midcycle luteinizing hormone and follicle-stimulating hormone surges.

The positive feedback effects of estradiol (E2) and progesterone (P) on LH and FSH release were studied under novel experimental conditions in three women of reproductive age who had undergone oophorectomy and received uninterupted E2 replacement by subdermal implants. Basal serum E2 levels were in the midfollicular phase range, while LH and FSH levels were normal or slightly elevated. Each volunteer underwent seven experiments at 2- to 4-week intervals, receiving im injections of increasing amounts of estradiol benzoate (E2B) alone and in combination with P. The time and dose of P (administered via P-impregnated polysiloxane intravaginal rings) were varied. In two of the seven experiments, P was given without E2B injections. In all three subjects, increasing serum E2 levels mimicking the preovulatory E2 peak were followed by a surge of LH but not of FSH. However, when serum P levels rose after an increase in serum E2 concentrations had occurred, the LH surge occurred earlier and was accompanied by an FSH peak. When serum P levels rose before serum E2 concentrations had risen or when P levels increased without a rise in serum E2, neither a serum LH nor FSH peak was observed. When administered concomitantly, E2B and P suppressed FSH but not LH levels, while P alone did not affect serum LH or FSH concentrations. These data indicate that an acute rise in serum E2 is a necessary condition for the midcycle LH and FSH surges, that P facilitates or blocks the positive feedback response of gonadotropin release in a time-dependent manner, and that P is required for the preovulatory FSH peak.     

Estrogen-androgen levels in aging men and women: therapeutic considerations.

The influence of aging on serum levels of gonadotropins (FSH and LH), testosterone and estradiol was studied in the following groups: 4 normal men (ages 30 to 50), 38 men with symptoms of the male climacteric (ages 51 to 84), 25 men with relative impotence (ages 31 to 50), 10 normal women (ages 24 to 31), and 6 menopausal women (ages 58 to 76). FSH and LH levels began to rise in men in their 40's, and the increase became more conspicuous in the later age decades. The degree of elevation was nowhere comparable to that observed in the aging women. In the male, the serum testosterone levels showed a progressive decrease from the fifth age decade onward, whereas in the female there was an increase after the menopause. Estradiol levels showed no significant change in the aged male, but they were somewhat higher than in the aged female. Exceptions to the low-testosterone and low-gonadotropin relationship were observed in individual cases and might be explained by relatively high estradiol values. Proper replacement therapy by means of estrogens for the postmenopausal female and androgens for the aging male is often of great benefit, physically and emotionally.     

TESTICULAR FUNCTION FOLLOWING IRRADIATION OF THE HUMAN PREPUBERTAL TESTIS

Testicular function was studied in ten men, aged between 17 and 36 years, who had received irradiation for a nephroblastoma during childhood. The dose of scattered irradiation to the testes ranged from 268 to 983 rad. Eight subjects had either oligo- or azoospermia (0 to 5.6 million/ml), seven of whom had an elevated serum follicle-stimulating hormone (FSH) level. One subject showed evidence of Leydig cell dysfunction with a raised serum luteinizing hormone level (LH) and a low plasma testosterone concentration. A second group of eight prepubertal males, aged between 8 and 14 years, were studied. These had also been irradiated for abdominal malignancies during childhood and received a similar dose of irradiation to the testis as the first group studied. The plasma testosterone levels were within the normal range for prepubertal boys in all eight. The mean gonadotrophin levels were not significantly different from the mean levels of normal prepubertal males. Thus irradiation-induced damage to the germinal epithelium in prepubertal boys produces raised FSH levels after puberty but not before it. We conclude, therefore, that inhibition has a minor role in the control of the prepubertal hypothalamic-pituitary testicular axis and its contribution to gonadal control of gonadotrophin secretion changes with sexual maturation.     

Release of LH and FSH after administration of synthetic LH-releasing hormone

To study the effect of synthetic leutenizing hormone-releasing hormone (LH-RH) follicle stimulating hormone-releasing hormone (FSH-RH) on the release of LH and FSH in the human being, a decapeptide, synthesized by the solid phase method, was injected into normal volunteers 21-36 years old. There were 3 untreated men, 2 untreated women, 3 men pretreated with ethinyl estradiol and 3 women pretreated with an oral contraceptive (lyndiol). The synthetic hormone ((pyro)Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) caused an increase in serum LH values over the control (p less than .01) with no difference between men and women in the amount of LH released. FH was also significantly (p less than .01) increased but to lower levels than LH. Pretreatment with sex steroids led to a decrease in FSH values (p less than .10). Since the hormone is readily synthesized in large quantities, clinical studies are now possible.     

Patterns of serum LH and FSH in response to 4-hour infusions of luteinizing hormone releasing hormone in normal women during menstrual cycle, on oral contraceptives, and in postmenopausal state.

Patterns of serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) in response to 4-hour infusions (1 mcg/min) of LH-releasing hormone in 16 normal women during the menstrual cycle, in 4 women on oral contraceptives (OCs), and in 3 postmenopausal women were investigated. A biphasic response of LH was observed in the follicular and luteal phases, with the response much larger in the latter (p .001). The largest LH response was observed during the periovulatory phase (p .001). Women on combined OCs studied between Cycle Days 11-14 showed a biphasic response intermediate in magnitude (p .05) between follicular and luteal phases with some blunting of the initial phase of secretion. FSH response was not clearly biphasic but was greatest in the periovulatory phase (p .001), intermediate in the luteal phase (p .01), and least in the follicular phase. In postmenopausal women, total output of LH was similar to the luteal phase and the output of FSH was equivalent to that at midcycle. These data support the concept that the biphasic response to LH to the prolonged infusion is present in women and that its magnitude and characteristics may be modulated by estradiol and progesterone levels.     

Abnormal follicle-stimulating hormone and luteinizing hormone patterns contrasting with normal estradiol and progesterone secretion in women with longstanding unexplained infertility

Six women with unexplained longstanding infertility and regular menstrual cycles were studied. All had luteal structures identified at laparoscopy on normal appearing ovaries and normal plasma androgen levels. Daily or every other day determinations of FSH, LH, estradiol (E2), and progesterone (P) were performed in one cycle. The results were compared to similar data obtained in five apparently normal women. All six infertile women had normal patterns of E2 secretion, with a characteristic midcycle rise, followed by a normal sustained elevation of plasma P. Contrasting with the above were grossly abnormal secretory patterns of FSH and LH in five of six patients. Two types of alterations were observed. 1) Four women had plasma LH persistently higher than FSH, with absolute LH concentrations above control levels in three. Midcycle LH surges were identifiable in all four, while a FSH surge was present in only one. The LH to FSH ratio was consistently above 2. 2) One patient had plasma FSH and LH levels fluctuating between high normal and the menopausal range. At midcycle, there was a synchronized rise of both FSH and LH though not as high as on other occasions in the same cycle. This was preceded by an E2 rise and followed by P elevation. The latter type (no. 2) of endocrine changes have been previously observed in much older women, during menopausal transition. The study indicates that normal E2 and P secretion, suggestive of normal ovarian function, may occur in the absence of characteristic FSH and LH patterns. The abnormal gonadotropin patterns may well be causally related to the patient's infertility.     

Annual cycle of pituitary and plasma gonadotropins and plasma sex steroids in a wild population of the toad, Bufo japonicus

Pituitary and plasma gonadotropins and plasma sex steroids of free-living toads, Bufo japonicus, were measured monthly from March 1981 to February 1982 and examined in relation to gonadal cycles. Toads were captured at Mizuno, Saitama Prefecture. Individual blood samples were collected by cardiac puncture within 3 min of capture in the field. In males, testicular weight was maximal in August. Plasma follicle-stimulating hormone (FSH) levels changed in association with testicular weight. Plasma androgen levels showed a small peak in November and a large peak in March just prior to breeding. Plasma luteinizing hormone (LH) levels changed in parallel with plasma androgen levels. In females, neither plasma FSH nor LH alone were correlated significantly with ovarian weight. However, ovarian and oviductal weights both correlated significantly with plasma steroid levels. Plasma estradiol levels showed a sharp peak in March, followed by a rapid decrease to the minimum in April. A gradual increase of estradiol occurred from July to November in parallel with an increase in ovarian weight. Changes in plasma progesterone and androgen levels in females resembled those for estradiol. However, the changes in progesterone were not so marked as in estradiol. Plasma androgen levels in females were especially high between January and March. In both sexes, the pituitary gonadotropin contents changed in parallel with plasma levels of both FSH and LH. The pituitary almost always contained more LH than FSH, while the reverse was true in the plasma in both sexes. In addition, plasma FSH levels increased markedly in early summer when plasma LH remained unchanged (males) or increased only slightly (females). These results indicate that the toad may serve as excellent material for the study of differential control of FSH and LH secretion.     

alpha-Subunit and gonadotropin responses to luteinizing hormone-releasing hormone in hyperprolactinemic women before and after bromocriptine

alpha-Subunit and gonadotropin responses to a LHRH infusion (0.2 micrograms/min) for 4 h were studied in eight hyperprolactinemic amenorrheic women, ages 23-40, and in five normal women in the early follicular phase of the menstrual cycle. Basal alpha-subunit and LH concentrations were comparable to normal women; however, basal FSH concentrations were significantly (P less than 0.05) lower. Peak serum alpha, LH, and FSH concentrations during the LHRH infusion were significantly higher than controls (P less than 0.01, P less than 0.05, and P less than 0.01, respectively). Gel chromatography of serum confirmed the presence of both free alpha-subunit and intact LH which had normal biological activity. Six of the women were restudied in the early follicular phase of the cycle after return of normal ovulatory function and normalization of serum PRL concentrations. During bromocriptine therapy, peak serum alpha, LH, and FSH concentrations decreased significantly (P less than 0.02, P less than 0.05, and P less than 0.001, respectively) and were comparable to control subjects. The changes in serum alpha and gonadotropin responses to the LHRH infusion during bromocriptine therapy occurred independently of the serum estradiol concentrations. Abnormalities in the regulation of alpha-subunit and gonadotropin secretion are present in hyperprolactinemia. These abnormalities reverse with bromocriptine therapy and may occur independently of changes in gonadal steroids.     

FAILURE OF POSITIVE FEEDBACK IN NORMAL MEN AND SUBJECTS WITH TESTICULAR FEMINIZATION

The abdity of the hypothalamic-pituitary unit to release luteinizing hormone (LH) in response to oestrogen Cpositive feedback) was studied in normal men and women and in subjects with testicular feminization or XY gonadal dysgenesis. Ethinyloestra-diol (200 μg a day for 3 days) given orally to six regularly menstruating women during the early to mid follicular phase of the cycle evoked an LH surge which started between 48 and 72 h after the initiation of treatment. A similar positive feedback effect on the secretion of follicle-stimulating hormone (FSH) could not be demonstrated. In eight normal men there was no evidence for a stimulatory effect of ethinyl-oestradiol (in doses of 200 μg or 500 μg a day for 3 days) on gonadotrophin release even though the levels of plasma ethyloestradiol in men on the higher dosage regime were greater than those found in women. Changes of peripheral LH, but not FSH, in men were inversely related to plasma ethinyloestradiol concentrations. A patient with XY pure gonadal dysgenesis exhibited a female type of LH release in response to ethinyloestradiol administration (200 μg a day for 3 days), but two patients with the syndrome of testicular feminization failed to release LH. The results suggest that normal adults of the two sexes differ in their ability to respond to ethinyloestradiol administration with LH release. The female response in XY gonadal dysgenesis emphasizes the importance of testicular secretions for the suppression of positive feedback whereas the male type of response in cases of testicular feminization indicates that testosterone does not represent the central mediator of this testicular function. The reported observations are compatible with the concept that the organizing action of the testes on positive feedback is mediated through 17β-oestradiol.     

Recovery of hormone secretion after chronic gonadotropin-releasing hormone agonist administration in women with polycystic ovarian disease

Persistent suppression of gonadotropin and ovarian steroid production can be achieved in women with polycystic ovarian disease (PCO) by daily administration of a long-acting GnRH agonist (GnRHa). This study was designed to determine the patterns of recovery of clinical responses and hormonal secretion after chronic GnRHa administration in women with PCO. Six women with PCO were treated with daily sc injections of [D-His6(imBzl),Pro9-NEt]GnRHa (100 micrograms) for 6 months. Blood samples were obtained at the time of and three times weakly for 90 days after discontinuation of agonist therapy. In five women who did not ovulate, the suppressed serum FSH levels rose to pretreatment values within 10 days. In contrast, a gradual and progressive increase in serum LH (as measured by bioassay and immunoassay) was apparent by day 18. The LH increase coincided with progressive increases in serum estrone (E1), androstenedione, and testosterone. Serum estradiol (E2) began to rise on day 28. All hormones returned to their pretreatment baseline values within the 90-day recovery interval, with the exception of E2. Trend analysis of the slopes of recovery revealed that the incremental secretion patterns of E1, E2, androstenedione, and testosterone differed significantly from that of FSH, but not from those of bioactive or immunoactive LH. Serum progesterone, dehydroepiandrosterone sulfate, and cortisol did not change after withdrawal of GnRHa. One woman ovulated spontaneously on day 52 before which her hormone secretion patterns were indistinguishable from those of the other women. In summary, 1) during recovery after discontinuation of chronic GnRH agonist therapy the patterns of FSH and LH release suggested resumption of endogenous GnRH action on the pituitary with greater release of FSH than LH, a pattern that would be expected in the absence of ovarian steroid influence; 2) the lack of early estrogen production despite the increase in serum FSH concentrations suggests inadequate FSH secretion, abnormal ovarian responsiveness to FSH, or impaired FSH bioactivity; 3) androgen secretion was provoked by the increase in LH secretion; 4) per unit LH measured by bioassay, greater ovarian androgen secretion was stimulated in PCO than ovulatory women; and 5) the likelihood of spontaneous ovulation during recovery was minimal.     

A separate mechanism of gonadotropin recovery after pregnancy termination

To further elucidate the mechanism of return of pituitary secretory function after gestation, eight women were studied for up to 55 days after pregnancy termination. As long as serum estradiol (E2) and progesterone (P) levels were elevated, serum FSH remained low. Four to 6 days after abortion, serum E2 and P decreased to levels seen in the early follicular phase, and thereafter the initial increase in FSH occurred while serum beta-LH remained undetectable. After the initiation of FSH secretion, the levels fluctuated within the normal follicular phase range, resulting in a steady increase of E2 to a mean preovulatory peak of 257 +/- 37 pg/ml at a mean time of 21 +/- 1.3 days after pregnancy termination. This E2 peak was followed by FSH and LH peaks and subsequent ovulation. In contrast to FSH, serum beta-LH levels increased only after PRL-concentrations diminished to 30 ng/ml or less. This initiation of beta-LH secretion followed the advent of FSH secretion in six of eight patients. Therefore, a temporally separate mechanism of FSH and LH secretion after pregnancy termination is theorized. The theory of FSH occurs soon after the E2 and P levels decline while PRL levels are still elevated. However, the secretion of beta-LH increases only after levels have risen from the postabortion decline.     

Serum hormones in human breast cancer subjects

Different serum hormones were studied in patients with benign breast diseases and breast carcinoma in respect of different phases of the menstrual cycle, as well as in postmenopausal women. In premenopausal breast carcinoma subjects 10% showed elevated serum estradiol alone, 7% showed elevated serum prolactin alone, and 12% subjects exhibited elevated levels of both serum estradiol and prolactin. Similarly, in postmenopausal breast carcinoma subjects 12% showed elevated serum estradiol alone, 10% showed elevated serum prolactin alone, and 22% exhibited elevated level of both serum estradiol and prolactin. On the other hand, in patients with benign breast disease only 5 showed an elevated level of prolactin alone. More than 50% of premenopausal women with carcinoma of the breast had low level of serum progesterone during the luteal phase as compared to normal subjects. No variations in serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were evident between normal subjects and women with breast carcinoma or benign breast disease. The increased level of serum estradiol and prolactin may be useful in the diagnosis of human breast cancer.