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Obstetrics & Gynecology 2000;96:243-249
© 2000 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Prolonged Endocrine Responses to Medroxyprogesterone in Postmenopausal Women With Respiratory Insufficiency

TARJA SAARESRANTA, MD, KERTTU IRJALA, MD, PhD, PÄIVI POLO-KANTOLA, MD, PhD, HANS HELENIUS, MSc and OLLI POLO, MD, PhD

From the Departments of Pulmonary Diseases, Obstetrics and Gynecology, and Clinical Chemistry, Turku University Hospital; and the Departments of Biostatistics and Physiology, Turku University, Turku, Finland.

Address reprint requests to: Tarja Saaresranta, MD Department of Pulmonary Diseases Turku University Hospital Kiinamyllynkatu 4–8 Turku FIN-20520 Finland E-mail: tarja.saaresranta{at}tyks.fi


   Abstract
Top
Abstract
Materials and Methods
 Results
 Discussion
 References
 
Objective: To evaluate the endocrinologic changes associated with, and possibly responsible for, prolonged ventilatory improvement after short-term medroxyprogesterone acetate (MPA) in chronic respiratory failure.

Methods: Fourteen postmenopausal women with permanent or previous episodic hypercapnic or hypoxemic respiratory failure were enrolled in a placebo-controlled, 12-week, single-mask trial including 14-day treatment periods with placebo and MPA (60 mg daily) and a 6-week follow-up. We evaluated the duration of MPA-induced alterations on serum concentrations of progesterone, estradiol, testosterone, FSH, LH, sex hormone–binding globulin (SHBG), and prolactin. Hormones were measured four times: at baseline, after 14 days with MPA, and during the washout on days 21 and 42.

Results: With MPA, FSH decreased 42.7% (P < .001, 95% confidence interval [CI] -54.2, -31.6), LH 62.1% (P < .01; 95% CI -81.0, -32.6), and SHBG 58.1% (P < .001; 95% CI -63.0, -43.9). Luteinizing hormone remained decreased (-28.7%; P < .01; 95% CI -42.0, -14.2) at the 3-week washout, whereas FSH and SHBG were back to pretreatment levels. Prolactin had a borderline initial increase of 23.5% (P= .097; 95% CI -3.5, 50.5) with MPA and a significant increase at the 3-week (31.9%; P < .05; 95% CI 1.0, 62.9) and 6-week (26.4%; P < .05; 95% CI 4.4, 48.3) washouts.

Conclusion: Medroxyprogesterone acetate 60 mg daily for 2 weeks has both immediate (FSH, LH, and SHBG), prolonged (LH), and rebound endocrinologic (prolactin) effects up to 6 weeks after treatment. The MPA-induced widespread endocrine aftereffects could explain the earlier reported prolonged ventilatory improvement.

Progestins stimulate ventilation1,2 and increase upper airway dilator muscle activity.3 The ventilatory effects of medroxyprogesterone acetate (MPA) have been thought to subside within 14 days after cessation of therapy.1 However, we have previously shown that MPA improves nocturnal ventilation and awake blood gases in postmenopausal women for up to 3 weeks after cessation of oral MPA ( Saaresranta T, Polo-Kantola P, Aittokallio T, Terho EO, Irjala K, Erkkola R, et al. Prolonged improvement with short-term progesterone in postmenopausal women with nocturnal hypercapnia [abstract]. Am J Respir Crit Care Med 1998;157:A57).4 The mechanisms of the sustained stimulatory effect on respiration are unknown. Sustained MPA serum concentrations and secondary endocrine effects are understandable when MPA is administered parenterally in a depot form.5,6 Because MPA is rapidly eliminated from the circulation after oral administration,7 indirect factors may explain the prolonged ventilatory stimulation.

The multiple locations of progesterone, estrogen, androgen, prolactin, and hCG/LH receptors suggest that these hormones might act locally in various tissues including trachea, lungs, brain, and brain stem.8–16 However, little is known about the extragonadal functions of these hormones.

To better understand the mechanisms of sustained respiratory stimulation ( Saaresranta et al. Am J Respir Crit Care Med 1998;157:A57),4 we evaluated the degree and duration of MPA-induced alterations in endocrine profiles in postmenopausal women with chronic respiratory insufficiency. We followed the serum levels of progesterone, estradiol (E2), testosterone, FSH, LH, sex hormone– binding globulin (SHBG), and prolactin (PRL).


   Materials and Methods
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Abstract
 Materials and Methods
Results
 Discussion
 References
 
The candidate recruitment was initiated by searching women with permanent or previous episodic respiratory failure who were born between 1921 and 1947. One hundred thirty-four women were identified from the Turku University Hospital database. After excluding deceased patients and patients using any alternative medicine, medication with known effects on the central nervous system, progestins except MPA given by the research team, long-term oxygen therapy, current smoking, and the absence of indicators of major diseases except cor pulmonale or pulmonary diseases, 23 remaining candidates were interviewed by phone. Fourteen were willing to participate in the study, two were excluded. During the recruitment period two new patients from Vakka-Suomi District Hospital fulfilled the criteria and were willing to participate. Finally, 14 postmenopausal women with permanent or previous episodic hypercapnic or hypoxemic respiratory failure could be enrolled.

The mean body mass index (BMI) at baseline was 26.7 kg/m2 (standard deviation [SD] 5.22) and remained unchanged during the trial.4 The criteria for postmenopausal status were age over 50 years, at least 2 years since last menstruation, and serum concentrations of FSH over 30 IU/L. One subject receiving vaginal estrogen therapy was allowed to continue her hormone replacement therapy (HRT).

Written informed consent was obtained from all patients. The protocol was approved by the Joint Commission on Ethics of Turku University and Turku University Central Hospital, and the National Agency for Medicines.

Because MPA has prolonged residual effects of unknown duration ( Saaresranta et al. Am J Respir Crit Care Med 1998;157:A57), a standard double-masked, placebo-controlled, crossover study was found inappropriate. Therefore, a 12-week, placebo-controlled, single-mask trial was applied. Seven days after the baseline visit, subjects started with placebo tablets for 14 days. A 7-day placebo washout period was then followed by MPA orally 30 mg twice daily for another 14 days. The follow-up period after treatment was 6 weeks. Blood samples for measurements of serum LH, FSH, E2, progesterone, testosterone, SHBG, and PRL were collected in seated subjects at 8 AM at baseline, after 2 weeks with MPA, and after a 3-week and a 6-week washout period. The measurements with MPA were made in the morning after the last evening MPA dose. The washout measurements were also performed in the morning, 3 and 6 weeks after cessation of MPA administration.

Thirty milligrams of oral MPA was administered twice in the evening, at 9 PM and 11 PM. This dosage regimen was used to achieve adequate MPA concentrations throughout the night. Placebo tablets were similar in appearance and were administered in a similar dosage regimen. Compliance was assessed by tablet count, patient interviews, and measurements of serum MPA concentrations.

Prolactin, LH, FSH, and SHBG were determined with time-resolved immunofluorometric assay (AutoDelfia; Wallac, Turku, Finland), E2, and progesterone with radioimmunoassay (Spectria; Orion Diagnostica, Turku, Finland). Testosterone was determined after diethylether extraction with a Spectria Testosterone RIA kit (Orion Diagnostica).

The analyses were started with assessment of distributions, variances, and evaluation of correlation structures of repeated measurements. Based on these evaluations, the overall comparisons between repeated measurements were performed with either nonparametric Friedman test (SHBG, E2, progesterone, and testosterone) or parametric analysis of variance of repeated measurements (LH, FSH, and PRL).17,18 The unstructured covariance structure (SHBG, E2, progesterone, testosterone, LH, and FSH), or compound symmetry heterogeneity covariance structure (PRL) was applied in these two parametric analyses of variance. Overall testing was followed by analysis of pairwise contrasts where three time points were compared with baseline. In nonparametric cases the testing was done with Wilcoxon rank-sum test and in parametric cases with F test. Bonferroni corrections were made in P values and confidence intervals (CIs). The calculation of the CIs in nonparametric cases was approximative interval for median of differences.19 P values less than .05 were interpreted as statistically significant. Statistical computing was performed with SAS System for Windows, release 6/12/1996 (SAS Inc., Cary, NC).


   Results
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Abstract
 Materials and Methods
 Results
Discussion
 References
 
Of 14 patients, 13 completed the trial. One subject discontinued because of fever and viral respiratory tract infection after her placebo treatment period. If the values of E2 or progesterone concentrations were under their detection limits, their concentrations were estimated to be 50% of the detection limit. These values were used when calculating the median concentrations at the 3- and 6-week washouts.

Three types of hormone follow-up profile could be identified. In the first profile, FSH, LH, and SHBG decreased with MPA and returned to baseline by the end of a 6-week follow-up (Figure 1Go). The second profile had marginal suppression (E2 and testosterone) with MPA and rebounded during the follow-up, and hormone levels did not return to baseline within 6 weeks after cessation of MPA administration (Figure 2Go). In the third profile (progesterone and PRL), there was an increase with MPA that continued during follow-up (Figure 3Go).



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  		Figure 1. Changes in FSH, LH, and sex hormone–binding protein (SHBG) with medroxyprogesterone acetate (MPA) and after 3-week and 6-week washouts. Mean and median changes are percentages from the baseline. Error bars indicate standard error of the mean. **P < .01. ***P < .001.

 


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  		Figure 2. Changes in estradiol and testosterone on medroxyprogesterone acetate (MPA) and after 3-week and 6-week washouts. Median changes are percentages from the baseline.

 


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  		Figure 3. Changes in progesterone and prolactin with medroxyprogesterone acetate (MPA) and after 3-week and 6-week washouts. Mean changes are percentages from the baseline. Error bars indicate standard error of the mean. *P < .05.

 
Medroxyprogesterone acetate induced a significant suppression in LH, FSH, and SHBG levels (Table 1Go and Figure 1Go). With MPA, FSH decreased 42.7% (P < .001; 95% CI -54.2, -31.6), LH 62.1% (P < .01; 95% CI -81.0,- 32.6), and SHBG 58.1% (P < .001; 95% CI -63.0,-43.9%). At 3 weeks after cessation of MPA, the mean LH still remained 7.7 U/L (SD 8.15; 95% CI -11.7, -3.6) or 28.7% (P < .01; 95% CI -42.0, -14.2) lower than at baseline, whereas at 6 weeks LH had returned to the baseline level (Table 1Go and Figure 1Go). The same pattern was seen in FSH and SHBG, but the prolonged decrease was not significant (Figure 1Go). Prolactin levels did not change significantly with MPA (+23.5%; P = .097; 95% CI -3.5, 50.5) but increased during follow-up by 31.9% (P < .05; 95% CI 1.0, 62.9) at the 3-week washout and by 26.4% (P < .05; 95% CI 4.4, 48.3) at the 6-week washout (Figure 3Go). The absolute changes in various hormone levels are shown in Table 1Go and the percent changes in Figures 1Go–3Go.


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  		Table 1. Mean or Median Values of Hormones at Baseline and Changes During and After Medroxyprogesterone Acetate Therapy
 

   Discussion
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Abstract
 Materials and Methods
 Results
 Discussion
References
 
Progestin therapy induces prolonged improvement in ventilation ( Saaresranta et al. Am J Respir Crit Care Med 1998;157:A57).4 The present study shows that in postmenopausal women with chronic respiratory insufficiency, 14-day MPA therapy induces prolonged endocrine changes. The sustained decrease in LH at the 3-week washout and the increase in PRL at the 3- and 6-week washouts show that MPA has effects that may persist several weeks after cessation of hormone therapy. These effects might be involved in improved ventilation.

The relationship between hormones and breathing is of special interest in view of the increased prevalence of sleep-disordered breathing after menopause.20 If the increased prevalence is related to the sharp decline in female hormones, postmenopausal HRT would be an option to treat breathing disorders in this patient group. Progestin-induced decline in SHBG results in an increase in the proportion of free E2 and testosterone. Estradiol is needed for upregulation of progesterone receptors21 which are also likely to mediate progesterone’s respiratory effects. If MPA is converted to estrogens,22 part of the upregulating estrogen might be derived from MPA molecules converted to estrogen. The duration of estrogen-induced upregulation of progesterone receptors is not known.

In postmenopausal women, testosterone and progesterone levels decrease in the same proportion.23 Therefore, it seems likely that a certain progesterone level is more crucial for protection against sleep-disordered breathing than the level of testosterone. The protective effect of progesterone is probably due to its capacity to increase upper airway dilator muscle activity3 and stimulate ventilation.1

Lundgren et al24 observed no decrease in serum progesterone in postmenopausal women receiving MPA for breast cancer. This was also our finding. Contradictory to our results, Petsos et al,25 like most investigators, observed MPA-induced suppression in serum progesterone in all but one subject. Our postmenopausal patients had very low progesterone concentrations at baseline; therefore, further decline observed in most studies was not possible.

In addition to the decline in estrogen and progesterone, other menopause-induced endocrine changes may also be involved. The respiratory effects of high FSH and LH levels in postmenopausal women are not known.26 Men with chronic obstructive lung disease have higher LH concentrations than controls.27 Some of them also have increased FSH levels.27 Medroxyprogesterone reduces the levels of LH and FSH but these changes have not been linked to changes in breathing.

Control of breathing varies during the normal menstrual cycle. It is not known whether this variation is determined only by variation in progesterone levels. The 2-week MPA therapy corresponds to the luteal phase of the menstrual cycle, and also suppresses LH and FSH levels. Suppression of FSH and SHBG on MPA was not maintained after cessation of MPA. The enhanced and prolonged decrease in LH compared with FSH is in line with the study of Petsos et al25 in women with polycystic ovary syndrome. In those women, MPA (MPA 10 mg/day for 14 days) decreased LH (mean 48% of basal) more than FSH (to 48% compared with 68% of basal levels). The suppressive effect of MPA on FSH was completely eliminated within 2 weeks after cessation of MPA and with LH within 4 weeks.25 The LH and FSH suppression was sustained for several weeks after termination of treatment. Because MPA is rapidly eliminated from the circulation after oral administration,7 the sustained suppression more likely reflects enhanced pituitary sensitivity than an effect of residual MPA. However, the effects of long-acting active metabolites of MPA cannot be excluded. Medroxyprogesterone acetate has many metabolites, the pharmacokinetics of which are not known. The turnover of MPA may also differ in various tissues. In rats, the MPA-related substances disappear slowly from the lung, skeletal muscle, and brain.28

Testosterone influences the control of breathing by increasing the hypoxic ventilatory response and metabolic rate.29 Testosterone also worsens sleep-disordered breathing.30 Androgens downregulate estrogen and progesterone receptors31 and increase estrone levels but do not alter progesterone or E2 levels.32 Progesterone receptors are essential for the action of progesterone; therefore, their downregulation by androgens may attenuate the respiratory stimulatory effect of progesterone. In our study, however, MPA did not suppress testosterone. Therefore, the changes in testosterone levels cannot explain the improved ventilation in the postmenopausal women in our study.

The acute MPA-induced suppression on SHBG is similar to what was found in previous studies showing that during MPA treatment serum SHBG decreases 25–68%,24,33 even with low (150 mg every 12 weeks in the depot form) doses.34 A number of hormones and other factors regulate the hepatic synthesis of SHBG. Androgens, glucocorticoids, high levels of insulin, growth hormone, insulin-like growth factor-1, PRL, and obesity decrease SHBG levels, whereas thyroid hormones, endogenous estrogens, oral exogenous estrogens, fasting, and cirrhosis increase them.35–38 In men SHBG increases with aging, but in women there are no consistent age-related changes.38–40 Medroxyprogesterone acetate has certain glucocorticoid-like properties that manifest as cortisol suppression.41 Thus, it is possible that MPA-induced decline in SHBG is due to its glucocorticoid-like effects. The reduction in SHBG levels leads to an increase in percentage of free testosterone and E2 in the circulation.35

In the present study, PRL levels increased after MPA. This is in agreement with observations in postmenopausal women receiving MPA 20 mg daily for 12 weeks42 and in patients with metastatic breast cancer receiving MPA in oral daily doses of 500–1500 mg.43 However, conflicting results have been published on changes in serum PRL levels during progestin treatment.24,43 Prolactin levels were low and near the detection limit throughout our trial. Therefore, the observed increase of PRL during the follow-up could be without biologic significance.

Prolactin presumably stimulates surfactant production in the lungs, which is considered by some to be a major target organ for PRL.14,15,44 Also, PRL may be involved in breathing in adults. In healthy premenopausal women, acute hypobaric hypoxia decreased basal PRL levels.45 Oxygen breathing increased serum concentrations of PRL in male athletes.46 However, hypoxic male patients with stable chronic obstructive pulmonary disease seem to have normal basal PRL levels.27,47

In postmenopausal women with chronic respiratory insufficiency, MPA 60 mg daily for 2 weeks decreases serum LH, FSH, and SHBG, and induces a rise in PRL after MPA therapy. The reduction in LH is maintained for at least 3 weeks. Our observations show that MPA has a prolonged effect on hormone profiles; therefore, other prolonged effects are also likely. These findings are in line with our previous observations of prolonged ventilatory improvement induced by MPA ( Saaresranta et al. Am J Respir Crit Care Med 1998;157:A57).4 Neither the site of action nor mechanisms of the prolonged ventilatory effect are known, but the present observations suggest that complex hormonal interactions are involved.


   Footnotes
 
This work was supported by grants from the Finnish Anti-Tuberculosis Association Foundation, the Väinö and Laina Kivi Foundation, and the Turku University Foundation. Medication was supplied by the drug company Orion, Espoo, Finland.

PII S0029-7844(00)00897-8

Received September 27, 1999. Received in revised form January 25, 2000. Accepted February 10, 2000.


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 Materials and Methods
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 Discussion
 References
 
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