Abstract:
The present invention is directed to a method for treating symptoms associated with premenstrual syndrome. The method comprises administering to an individual in need of treatment an amount of a combination of elemental calcium and vitamin D effective to reduce the symptoms associated with premenstrual syndrome.

Description:
TECHNICAL FIELD 
     This is a continuation-in-part of application Ser. No. 07/945,319 filed Sep. 15, 1992, by the same inventor now U.S. Pat. No. 5,354,743. 
    
    
     BACKGROUND OF THE INVENTION 
     This invention relates to a method for reducing or relieving symptoms associated with premenstrual syndrome (“PMS”) by administering to an individual exhibiting PMS symptomology a therapeutically effective amount of a combination of calcium and vitamin D. 
     BACKGROUND OF THE ART 
     Symptoms generally experienced by women with PMS, the occurrence and exaggeration of mood and behavioral disturbances in women during the latter half of their menstrual cycle, without limitation include (1) somatic symptoms such as abdominal cramps, headaches including vascular headaches such as migraine headaches, breast fullness and tenderness, back pain and bloating and (2) psychological symptoms such as, depression, irritability and anxiety. While these symptoms, which are among those generally related to PMS, do not occur solely in women with PMS, it has been estimated that as much as 90% of all premenopausal women exhibit some degree of symptoms such as those above related to PMS, ranging from mild to incapacitating, and that about 7 million women suffer severe and incapacitating symptoms related to PMS. 
     U.S. Pat. No. 4,946,679 of Thys-Jacobs and the article by Thys-Jacobs et al. entitled “Calcium Supplementation in Premenstrual Syndrome. A Randomized Crossover Trial”,  J. Gen. Int. Med.,  1989:4:183, showed that elemental calcium is effective in significantly reducing symptoms associated with PMS when administered, for example, in a daily dose of 1000 mg for 3 months. Thys-Jacobs et al. reported a 50% reduction in PMS symptomology for the daily administration of elemental calcium in the dose of 1000 mg for three months. Similarly, Chuong et al., in an abstract presented at the American Fertility Annual Meeting in 1991 entitled “Calcium Levels in Premenstrual Syndrome” showed that women with PMS had significantly lower calcium levels during the luteal phase of the menstrual cycle as compared with asymptomatic controls and also showed that women with PMS had significantly lower calcium levels during the luteal phase of the menstrual cycle as compared to the follicular phase of the menstrual cycle. 
     However, there still exists a need for therapy that provides further reduction or relief of symptoms associated with PMS, especially in particularly persistent cases. 
     SUMMARY OF THIS INVENTION 
     An object of this invention is to reduce or relieve symptoms associated with PMS in an individual exhibiting such symptoms, especially in those patients who do not demonstrate improvement when treated with calcium alone. 
     The present invention is directed to a method of at least reducing symptoms associated with PMS. A therapeutically effective amount of a combination of calcium and vitamin D is administered to an individual exhibiting symptomatology associated with PMS. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The method of the present invention treats individuals exhibiting symptoms associated with PMS by the administration of a therapeutically effective amount of a combination of calcium and vitamin D. Preferably, the dosage of elemental calcium administered is in the range of from about 1000 mg to about 2000 mg per day. Preferably, the dosage of vitamin D administered is in the range of from about 400 to about 2000 IU per day. Preferably, the dosage of vitamin D elevates 25 hydroxyvitamin D levels to levels greater than 30-40 ng/ml. The calcium and vitamin D may be administered concurrently such as, for example, by administration of a tablet, a capsule, a powder, liquid, candy or mint, cookie or food additive containing the desired dosages of the calcium and the vitamin D. Preferably, the combination is administered orally in the form of a tablet. Calcium may be administered in the form of calcium carbonate, calcium gluconate, calcium citrate, calcium phosphate, calcium chloride, calcium stearate or calcium acetate, and preferably in the form of calcium carbonate. Vitamin D may be administered as at least one of vitamin D 2  (ergocalciferol), vitamin D 3  (cholecalciferol) or 25 hydroxyvitamin D (calcidiol or calcifediol). The dose can be taken as a single daily combination dose or in split doses of smaller concentrations in adequate levels for prevention of PMS symptoms. Examples of combinations for single doses are as follows: 
     
       
         
               
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Elemental calcium 
                 Vitamin D 2  or D 3   
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 1000 
                 mg 
                 400 
                 IU 
               
               
                 1000 
                 mg 
                 600 
                 IU 
               
               
                 1000 
                 mg 
                 800 
                 IU 
               
               
                 1200 
                 mg 
                 400 
                 IU 
               
               
                 1200 
                 mg 
                 600 
                 IU 
               
               
                 1200 
                 mg 
                 800 
                 IU 
               
               
                 1200 
                 mg 
                 1000 
                 IU 
               
               
                 1200 
                 mg 
                 1200 
                 IU 
               
               
                 1500 
                 mg 
                 400 
                 IU 
               
               
                 1500 
                 mg 
                 300 
                 IU 
               
               
                 1500 
                 mg 
                 800 
                 IU 
               
               
                 1500 
                 mg 
                 1000 
                 IU 
               
               
                 1500 
                 mg 
                 1200 
                 IU 
               
               
                 1500 
                 mg 
                 2000 
                 IU 
               
               
                   
               
             
          
         
       
     
     Examples of smaller concentration embodiments to be administered at least 2 to 3 times daily are as follows: 
     
       
         
               
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Elemental calcium 
                 Vitamin D 2  or D 3   
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 300 
                 mg 
                 200 
                 IU 
               
               
                 300 
                 mg 
                 250 
                 IU 
               
               
                 500 
                 mg 
                 200 
                 IU 
               
               
                 500 
                 mg 
                 300 
                 IU 
               
               
                 500 
                 mg 
                 400 
                 IU 
               
               
                 600 
                 mg 
                 300 
                 IU 
               
               
                 600 
                 mg 
                 400 
                 IU 
               
               
                 600 
                 mg 
                 500 
                 IU 
               
               
                 600 
                 mg 
                 600 
                 IU 
               
               
                 700 
                 mg 
                 700 
                 IU 
               
               
                 800 
                 mg 
                 400 
                 IU 
               
               
                 800 
                 mg 
                 800 
                 IU 
               
               
                 800 
                 mg 
                 800 
                 IU 
               
               
                 2000 
                 mg 
                 2000 
                 IU 
               
               
                   
               
             
          
         
       
     
     The combination is effective for reducing or relieving symptoms associated with PMS, which include somatic symptoms such as without limitation headaches, especially vascular headaches such as migraine headaches, tenderness and swelling of the breasts, abdominal bloating, abdominal cramping, generalized aches and pains, lower backache, fatigue, increased/decreased appetite, craving for sweet/salt, swelling or edema of extremities and insomnia and which include psychological symptoms such as mood swings, depression, tension, anxiety, anger and crying spells. 
     The foregoing and other objects, features, aspects and advantages of the present invention will become more apparent from the following detailed non-limiting examples of the present invention. 
    
    
     EXAMPLE 1 
     Applicant&#39;s Research Study Indicating That Many Women With PMS Have A Vitamin D Deficiency 
     1.1 Enrollment of Participants 
     The study herein described was conducted at Mount Sinai Hospital in New York City. Women working and residing in the New York area with a self-diagnosis of PMS were recruited. 
     From those women reporting a self-diagnosis of PMS, women were further selected if they fulfilled a strict definition of premenstrual syndrome: Cyclically recurring symptoms during the luteal phase of the menstrual cycle which subside with the onset of menstruation. Determination of recurrence of symptoms was based on a prospective and consecutive two month daily diary. Each woman was asked to complete daily pre-trial self-assessment questionnaires where 17 symptoms were measured and recorded daily over one menstrual cycle. Each was instructed to complete one questionnaire every evening, describing how she felt during the previous 24 hours by recording her level of symptom severity for each of the seventeen symptoms. The 17 symptoms evaluated were: mood swings, depression, tension, anxiety, anger, crying spells, tenderness and swelling of breasts, abdominal bloating, abdominal cramping, generalized aches and pains, low backache, headache, fatigue, increased/decreased appetite, cravings for sweet/salt, swelling/edema of extremities and insomnia. Each symptom was marked daily on a four-point scale (absent, mild, moderate, severe) and subsequently scored from 0 to 3. Women were further selected if their mean symptom scores from the latter seven days of the luteal phase were at least 50% greater than the seven days following the days of menstruation. 
     Criteria for exclusion from the clinical trial were: (1) history of renal disease, (2) history of primary hyperparathyroidism, (3) history of liver or gastrointestinal disease, (4) history of endometriosis, (5) history of psychosis and (6) active depression. 
     22 women were finally selected for this study. A preliminary evaluation on each finally selected woman (“patient”) included (1) a standardized medical evaluation with a detailed gynecological history as well as a routine physical examination and (2) a determination of complete blood count, electrolytes, alkaline phosphatase, albumin, glucose and urinalysis. All determinations of the above were within normal laboratory limits as set by the laboratory performing the determinations. 
     1.2 Study 
     For all women baseline levels for calciotropic hormones 1,25 dihydroxyvitamin D [1,25(OH) 2 D], 25 hydroxyvitamin D [250HD] and intact parathyroid hormone (iPTH) were determined at the midpoint in the menstrual cycle. Additionally, baseline calcium levels were determined at the midpoint in the menstrual cycle. All determinations and evaluations of serum samples were performed by a single central laboratory, Nichols Institute of California. 
     Serum samples for the 1,25(OH) 2 D assay were extracted with acetonitrile and purified by Sep-pak C-18 and Sep-Pak silica columns. The purified 1,25(OH) 2 D was assayed in a radioreceptor assay using calf thymus and  3 H-1,25(OH) 2 D. 
     The serum samples for the 250HD assay, like the 1,25(OH) 2 D samples, were extracted with acetonitrile and purified through C-18 Sep-Pak columns. The purified 250HD sample was assayed in a radiobinding assay using  3 H-250HD and rat serum binding protein. 
     The intact parathyroid hormone assay is a two site immunoradiometric assay (IRMA). The IRMA employs two kinds of anti sera, one is specific to the C-terminal portion of the molecule and the other is specific to the N-terminal end. The assay measures only the intact hormone. 
     The serum samples for total calcium were assayed by atomic absorption spectrometry. 
     The results are shown below in Table 1. Normal values for the calciotropic hormones 1,25(OH) 2 D, 250HD and intact parathyroid hormone (iPTH) and calcium are shown below in Table 2. 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 CALCIOTROPIC HORMONES IN WOMEN 
               
               
                 WITH PREMENSTRUAL SYNDROME 
               
             
          
           
               
                   
                   
                 250HD 
                 T.calcium 
                 iPTH 
                 1,25(OH) 2 D 
               
               
                 Patient 
                 Cycle Day 
                 ng/ml 
                 mg/dl 
                 pg/ml 
                 pg/ml 
               
               
                   
               
             
          
           
               
                 001 
                 14 
                 18 
                 9.6 
                 71 
                 46 
               
               
                 002 
                 12 
                 17 
                 9.6 
                 46 
                 60 
               
               
                 003 
                 15 
                 20 
                 8.7 
                 70 
                 38 
               
               
                 004 
                 13 
                 24 
                 9.5 
                 25 
                 51 
               
               
                 005 
                 12 
                 17 
                 9.1 
                 68 
                 &lt;5 
               
               
                 006 
                 15 
                 16 
                 9.6 
                 49 
                 52 
               
               
                 007 
                 15 
                 16 
                 8.8 
                 30 
                 69 
               
               
                 008 
                 13 
                 17 
                 8.9 
                 86 
                 75 
               
               
                 009 
                 17 
                 27 
                 9.3 
                 61 
                 57 
               
               
                 010 
                 16 
                 24 
                 8.9 
                 60 
                 36 
               
               
                 011 
                 13 
                 33 
                 9.4 
                 54 
                 46 
               
               
                 012 
                 14 
                 25 
                 9.4 
                 50 
                 46 
               
               
                 013 
                 14 
                 19 
                 9.4 
                 65 
                 44 
               
               
                 014 
                 15 
                 27 
                 9.8 
                 66 
                 50 
               
               
                 015 
                 13 
                 21 
                 9.3 
                 47 
                 84 
               
               
                 016 
                 13 
                 27 
                 10.0 
                 26 
                 40 
               
               
                 017 
                 15 
                 23 
                 9.0 
                 21 
                 21 
               
               
                 018 
                 14 
                 27 
                 9.6 
                 31 
                 51 
               
               
                 019 
                 14 
                 35 
                 9.3 
                 39 
                 63 
               
               
                 020 
                 14 
                 24 
                 9.3 
                 21 
                 54 
               
               
                 021 
                 15 
                 21 
                 8.9 
                 48 
                 15 
               
               
                 022 
                 15 
                 21 
                 9.0 
                 32 
                 32 
               
               
                   
               
               
                 Cycle day refers to the day of the menstrual cycle when the serum sample was drawn.  
               
               
                 T.calcium refers to total calcium.  
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 NORMAL CALCIOTROPIC HORMONE VALUES 
               
               
                 AS DETERMINED BY LABORATORY 
               
             
          
           
               
                   
                 250HD 
                 T.calcium 
                 iPTH 
                 1,25(OH) 2 D 
               
               
                   
                 ng/ml 
                 mg/dl 
                 pg/ml 
                 pg/ml 
               
               
                   
                   
               
             
          
           
               
                 Normal 
                 9-52 
                 8.8-10.4 
                 10-65 
                 15-60 
               
               
                 Values 
               
               
                   
               
             
          
         
       
     
     1.3 Discussion of Lab Results 
     Only one patient was determined to be hypocalcemic. Five women were determined to have elevated iPTH determinations, while five were determined to have abnormal 1,25(OH) 2 D levels with four elevated and one undetectable. All were determined to have normal 250HD levels. Thus, a total of ten women were determined to have abnormally elevated iPTH or 1,25(OH) 2 D determinations when these measurements were drawn at the midpoint of the menstrual cycle. It has been mentioned by Nordin et al. in an article entitled “Osteoporosis and Osteomalacia” in  Clin. Endocrinal Metab.,  1980; 9; 177-205 that a raised iPTH level might indicate a vitamin D deficiency. Five women were determined to have elevated iPTH levels and might be considered vitamin D deficient. However, elevated iPTH is a necessary but not a sufficient condition to absolutely diagnose a vitamin D deficiency. 
     1.4 Treatment 
     Each woman was instructed to take daily supplementation with 600 to 2000 IU per day of vitamin D 2  or D 3  and 1200 mg to 1500 mg per day of elemental calcium. 
     1.5 Results 
     Daily supplementation with vitamin D in doses of 600 to 2000 IU per day and with elemental calcium in doses of 1200 mg to 1500 mg per day resulted in a significant relief of PMS symptomology. Within months this therapy resulted in an elevation of the 250HD level above 30-40 ng/ml, and for those women with abnormal calciotropic values as defined by the laboratory, such values were corrected to within normal determinations. To prevent recurrence each was instructed to continue lifetime vitamin D and calcium supplementation. 
     EXAMPLE 2 
     Case Studies Applying Applicant&#39;s Research Finding 
     2.1 Patient X 
     Patient X is a 47 year old female with a 20 year history of PMS. Her major symptoms included severe irritability, mood swings, breast swelling and tenderness, and menstrual cramps. Vascular headaches, specifically common migraines (or migraines without aura), frequently interfered with her functional well being during both the premenstrual and menstrual phases of her menstrual cycle. She occasionally suffered with classic migraines (or migraines with aura) at least 4 to 5 times a year. Her common migraines were characterized by a pulsating quality of severe intensity lasting 2-3 days, associated with photophobia, nausea, occasional vomiting, and exacerbated by routine physical activity. These migraines were temporally related to the onset of her menstrual period and were always associated with her PMS symtomatology. Her past medical history was significant for mild hypertension, polycystic kidney disease, mitral valve prolapse with mitral regurgitation, recurrent vaginitis, and amenorrhea 22 years ago. She had a very strong family history of breast cancer with a mother, aunt and sister all diagnosed with cancer. She is at major risk for the development of breast cancer with such a strong family history of breast cancer, a personal history of cyclical mastopathy, and a residence in the New England region. She requires an annual mammogram and breast examination for cancer screening. 
     Calciotropic hormone levels in this patient: 
     4/92: total calcium 8.5 mg/dl (8.6-10.1) 
     iPTH—8.5 pmol/L (1.0-6.8) 
     250HD—14 mcg/L (10-80) 
     1,25(OH) 2 D—30.3 ng/L (18.0-62.0) 
     7/92: total calcium 9.10 mg/dl (8.6-10.1) 
     11/92: total calcium 9.00 mg/dl (8.6-10.1) 
     iPTH—7.3 pmol/L (1.0-6.8) 
     250HD—30.3 mcg/L (10.0-80.0) 
     1,25(OH) 2 D—50.1 ng/L (18.0-62.0) 
     2/93: total calcium 9.70 mg/dl (8.6-10.1) 
     iPTH—4.30 pmol/L (1.0-6.8) 
     250HD—34.5 mcg/L (10-80) 
     She was diagnosed with PMS by history, by prospective charting of symptoms and by a luteal to intermenstrual ratio of greater than 150%. Laboratory results confirmed hypocalcemia with a secondary hyperparathyroidism and a normal 250HD. In 4/92, she was treated with elemental calcium in the dose of 1200 mg/day and continued on her daily multivitamins (which included a low dose of elemental calcium and the RDA for vitamin D). Over the next 2 months, this resulted in complete correction of her hypocalcemia, but only partial relief of her premenstrual irritability and menstrual cramps. She was then prescribed 400 additional IU of cholecalciferol, while elemental calcium was increased to 1500 mg per day. Her vascular headaches persisted, and she still complained of nocturnal menstrual cramps. In 11/92, her total calcium was normal, her iPTH was elevated and her 250HD remained normal as defined by the laboratory. She was prescribed 1000 IU of cholecalciferol per day and maintained on 1500 mg of elemental calcium per day in addition to her daily multivitamin (total vitamin D intake therefore amounted to 1200 IU). On this regimen, her iPTH normalized, her 250HD increased to 34.5 mcg/L and her symptoms resolved. In addition, her blood pressure normalized. By recommending appropriate doses of vitamin D and calcium, and maintaining the 250HD level above 35.0 mcg/L with semiannual determinations, symptomatology was prevented. 
     2.2 Patient Y 
     Y is a 47 year old female with a history of Rheumatic fever, mild hypertension and a 30 year history of PMS. She presented with severe premenstrual and menstrual symptomatology occurring 10 to 14 days prior to the onset of her menstrual period. Her symptoms consisted of anxiety, extreme nervousness, breast tenderness and fullness, abdominal bloating, body aches, lack of energy, vascular headaches, and severe menstrual cramps. Her symptoms were of such severity that her co-workers at her job ostracized her, and criticized her monthly abnormal behavior. With prospective charting of the daily symptoms described in Example 1.1 (less insomnia) over two menstrual cycles, PMS was confirmed. Her luteal mean score was 48 (the maximum achievable score). Baseline total calcium was 9.9 ng/ml (8.8-10.4), 250HD was 24 ng/ml (9-52) and iPTH was 54 pg/ml (10-65). Laboratory determinations showed that she had a serum calcium that was normal as defined by the laboratory, a vitamin D level that was normal, and a iPTH that was normal. Prescribed daily treatment with 1200 mg of elemental calcium and 800 IU of cholecalciferol completely resolved her headaches, abdominal cramps, irritability, lethargy, breast tenderness/fullness, and behavioral changes. 
     The present invention is not to be limited in scope by the embodiments disclosed in the examples which are intended as illustrations of aspects of the invention. Any methods which are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.